WO2002096927A2

WO2002096927A2 - Ribozyme based treatment of female reproductive diseases

Info

Publication number: WO2002096927A2
Application number: PCT/US2002/017674
Authority: WO
Inventors: Jaime Escobedo; James Mcswiggen; Pamela Pavco; Dan Stinchcomb; Jennifer Sandberg; Gilad Gordon
Original assignee: Ribozyme Pharmaceuticals, Incorporated; Chiron Corporation
Priority date: 2001-05-29
Filing date: 2002-05-29
Publication date: 2002-12-05
Also published as: EP1390385A2; JP2005500025A; GB0404461D0; EP1390385A4; WO2002096927A3; AU2002344237B8; CA2448320A1; AU2002344237B2; JP2009000106A

Abstract

The present invention relates to nucleic acid molecules, including dsRNA, siRNA, antisense, 2,5-A chimeras, aptamers, and enzymatic nucleic acid molecules, such as hammerhead ribozymes, DNAzymes, and allozymes, which modulate the expression of vascular endothelial growth factor receptor (VEGF) and/or vascular endothelial growth factor receptor (VEGFr) genes for the treatment and/or diagnosis of diseases and conditions associated with angiogenesis, such as cancer, tumor angiogenesis, or ocular indications such as diabetic retinopathy, or age related macular degeneration, proliferative diabetic retinopathy, hypoxia-induced angiogenesis, rheumatoid arthritis, psoriasis, wound healing, and female reproductive disorders and conditions, including but not limited to endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), and menopausal dysfunction.

Description

NUCLEIC ACID BASED MODULATION OF FEMALE REPRODUCTIVE DISEASES

AND CONDITIONS

This patent application claims priority from Sandberg et al, USSN 60/334,461, filed November 30, 2001, entitled "Method and Reagent for the Modulation of Female Reproductive Diseases and Conditions" and Pavco et al., USSN 10/138,674, filed May 3, 2002, which is a continuation in part of Pavco et al., USSN 09/870,161, which is a continuation-in-part of Pavco et al, USSN 09/708,690, filed November 7, 2000, which is a continuation-in-part of Pavco et al, USSN 09/371,722, filed August 10, 1999, which is a continuation-in-part of Pavco et al, USSN 08/584,040, filed January 11, 1996, which claims the benefit of Pavco et al, USSN 60/005,974, filed on October 26, 1995; these earlier applications are entitled "Method and Reagent for Treatment of Diseases or Conditions Related to Levels of Vascular Endothelial Growth Factor Receptor". Each of these applications is hereby incorporated by reference herein in it's entirety including the drawings and tables.

Technical Field Of The Invention

This invention relates to methods and reagents for the treatment of diseases or conditions relating to the levels of expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor(s). Specifically, the instant mvention features nucleic-acid based molecules and methods that modulate the expression of vascular endothelial growth factor and/or vascular endothelial growth factor receptors, such as VEGFR1 and or VEGFR2, that are useful in preventing, treating, controlling and/or diagnosing disorders and conditions related to angiogenesis, including but not limited to cancer, tumor angiogenesis, or ocular indications such as diabetic retinopathy, or age related macular degeneration, proliferative diabetic retinopathy, hypoxia-induced angiogenesis, rheumatoid arthritis, psoriasis, wound healing, endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), and menopausal dysfunction.

Background Of The Invention

The following is a discussion of relevant art, none of which is admitted to be prior art to the present invention. VEGF, also referred to as vascular permeability factor (VPF) and vasculotropin, is a potent and highly specific mitogen of vascular endothelial cells (for a review see Ferrara, 1993 Trends Cardiovas. Med. 3, 244; Neufeld et al, 1994, Prog. Growth Factor Res. 5, 89). VEGF-induced neovascularization is implicated in various pathological conditions such as tumor angiogenesis, or ocular indications such as diabetic retinopathy, or age related macular degeneration, proliferative diabetic retinopathy, hypoxia-induced angiogenesis, rheumatoid arthritis, psoriasis, wound healing and others.

VEGF, an endothelial cell-specific mitogen, is a 34-45 kDa glycoprotein with a wide range of activities that include promotion of angiogenesis, enhancement of vascular- permeability and others. VEGF belongs to the platelet-derived growth factor (PDGF) family of growth factors with approximately 18% homology with the A and B chain of PDGF at the amino acid level. Additionally, VEGF contains the eight conserved cysteine residues common to all growth factors belonging to the PDGF family (Neufeld et al, supra). VEGF protein is believed to exist predominantly as disulfide-lihked homodimers; monomers of VEGF have been shown to be inactive (Plouet et al, 1989 EMBO J. 8, 3801).

VEGF exerts its influence on vascular endothelial cells by binding to specific high- affinity cell surface receptors. Covalent cross-linking experiments with ¹²⁵I-labeled VEGF protein have led to the identification of three high molecular weight complexes of 225, 195 and 175 kDa presumed to be VEGF and VEGF receptor complexes (Vaisman et al, 1990 J Biol. Chem. 265, 19461). Based on these studies VEGF-specific receptors of 180, 150 and 130 kDa molecular mass were predicted. In endothelial cells, receptors of 150 and 130 kDa have been identified. The VEGF receptors belong to the superfamily of receptor tyrosine kinases (RTKs) characterized by a conserved cytoplasmic catalytic kinase domain and a hydrophilic kinase sequence. The extracellular domains of the VEGF receptors consist of seven immunoglobulin-like domains that are thought to be involved in VEGF binding functions.

The two most abundant and high-affinity receptors of VEGF are flt-1 (VEGFR1) (fins- like tyrosine kinase) cloned by Shibuya et al, 1990 Oncogene 5, 519 and KDR (VEGFR2) (kinase-insert-domain-containing receptor) cloned by Terman et al, 1991 Oncogene 6, 1677. The murine homolog of KDR, cloned by Mathews et al, 1991, Proc. Natl. Acad. Sci, USA, 88, 9026, shares 85% amino acid homology with KDR and is termed as flk-1 (fetal liver kinase- 1). The high-affinity binding of VEGF to its receptors is modulated by cell surface- associated heparin and heparin-like molecules (Gitay-Goren et al, 1992 J. Biol. Chem. 267, 6093). VEGF expression has been associated with several pathological states such as tumor angiogenesis, several forms of blindness, rheumatoid arthritis, psoriasis and others. In addition, a number of studies have demonstrated that VEGF is both necessary and sufficient for neovascularization. Takashita et al, 1995 J. Clin. Invest. 93, 662, demonstrated that a single injection of VEGF augmented collateral vessel development in a rabbit model of ischemia. VEGF also can induce neovascularization when injected into the cornea. Expression of the VEGF gene in CHO cells is sufficient to confer tumorigenic potential to the cells. Kim et al, supra and Millauer et al, supra used monoclonal antibodies against VEGF or a dominant negative form of VEGFR2 receptor to inhibit tumor-induced neovascularization.

During development, VEGF and its receptors are associated with regions of new vascular growth (Millauer et al., 1993 Cell 72, 835; Shalaby et al., 1993 J. Clin. Invest. 91, 2235). Furthermore, transgenic mice lacking either of the VEGF receptors are defective in blood vessel formation and these mice do not survive; VEGFR2 appears to be required for differentiation of endothelial cells, while VEGFRl appears to be required at later stages of vessel formation (Shalaby et al., 1995 Nature 376, 62; Fung et al., 1995 Nature 376, 66). Thus, these receptors apparently need to be present to properly signal endothelial cells or their precursors to respond to vascularization-promoting stimuli.

Increasing evidence suggests that the VEGF family may also be involved with both the etiology and maintenance of peritoneal endometriosis. Peritoneal endometriosis is a significant debilitating gynecological problem of widespread prevalence. It is now generally accepted that the pathogenesis of peritoneal endometriosis involves the implantation of exfoliated endometrmm. Maintenance of exfoliated endometrial tissue is dependent upon the generation and maintenance of an extensive blood supply both within and surrounding the ectopic tissue.

Endometriosis is a disease affecting an estimated 77 million women and teenagers worldwide. Endometriosis is a leading cause of infertility, chronic pelvic pain and hysterectomy. Endometriosis can be characterized when endometrial tissue (the tissue inside the uterus which builds up and is shed each month during menses) is found outside the uterus, in other areas of the body. The endometrial tissue can respond to hormonal commands each month and break down and bleed. However, unlike the endometrium, these tissue deposits have no way of leaving the body. The result is internal bleeding, degeneration of blood and tissue shed from the growths, inflammation of the surrounding areas, expression of irritating enzymes and formation of scar tissue. In addition, depending on the location of the growths, interference with the bowel, bladder, intestines and other areas of the pelvic cavity can occur. Endometrial tissue has even been found lodged in the skin and at other extrapelvic locations like the arm, leg and even brain.

Currently, the presence of Endometriosis can only be confirmed through surgery such as laparoscopy, but can be suspected based on symptoms, physical findings and diagnostic tests. Endometriosis can be treated in many different ways, both surgically and medically. Most commonly, surgery will be performed during which the disease will be excised, ablated, fulgarated, cauterized or otherwise removed, and adhesions will also be freed. Surgeries include but are not limited to laparoscopy; laparotomy; presacral and uterosacral and various levels of hysterectomies, where some or all of the reproductive organs are removed. Often, this method will only relieve the symptoms associated with growths on the reproductive organs, not the bowels or kidneys and related areas where Endometriosis can be present.

There are several drugs used to treat Endometriosis that are utilized either alone or in combination with surgery. These include contraceptives, GnRH agonists, and/or synthetic hormones. GnRH agonists are commonly used on women in all stages of the disease and may sometimes have serious side affects. GnRH (gonadotropin releasing hormone) analogues are classified into 2 groups: agonists and antagonists. Agonists are commonly used in the treatment of Endometriosis by suppressing the manufacture of follicle stimulating hormone (FSH) and luteinizing hormone (LH), common hormones required in ovulation. When they are not secreted, the body will go into "pseudo-menopause," stalling the growth of more implants. However, these are again only stop-gap measures that can be utilized only for short term intervals. Once the body returns to it's normal state, the Endometriosis will again begin to implant itself.

Angiogenesis is likely to be involved in the pathogenesis of endometriosis. According to the transplantation theory, when the exfoliated endometrium is attached to the peritoneal layer, the establishment of a new blood supply is essential for the survival of the endometrial implant and development of endometriosis (Donnez et al, 1998, Hum. Reprod., 13, 1686- 1690). Endometrial growth and repair after menstruation are associated with profound angiogenesis. Abnormalities in these processes result in excessive or unpredictable bleeding patterns and are common in many women. It is therefore important to understand which factors regulate normal endometrial angiogenesis. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that plays an important role in normal and pathological angiogenesis (Fasciani et al, 2000, Mol. Hum. Reprod., 6, 50-54; Sharkey et al, 2000, J. Clin. Endocrinol. Metab., 85, 402-409). Sources of this factor include the eutopic endometrium, ectopic endometriotic tissue and peritoneal fluid macrophages. Important to its etiology is the correct peritoneal environment in which the exfoliated endometrium is seeded and implants. Established ectopic tissue is then dependent on the peritoneal environment for its survival, an environment that supports angiogenesis. The increasing knowledge of the involvement of the VEGF family in endometriotic angiogenesis raises the possibility of novel approaches to its medical management, with particular focus on the anti-angiogenic control of the action of VEGF (McLaren, 2001, Hum. Reprod. Update, 6, 45-55).

Pavco et al, International PCT Publication No. WO 97/15662, describes methods and reagents for treating diseases or conditions related to levels of vascular endothelial growth factor receptor.

Robinson, International PCT Publication No. WO 95/04142, describes the use of certain antisense oligonucleotides targeted against VEGF RNA to inhibit VEGF expression.

Jellinek et al, 1994 Biochemistry 33, 10450 describe the use of specific VEGF-specific high-affinity RNA aptamers to inhibit the binding of VEGF to its receptors.

Rockwell and Goldstein, International PCT Publication No. WO 95/21868, describe the use of certain anti-VEGF receptor monoclonal antibodies to neutralize the effect of VEGF on endothelial cells.

Pappa, International PCT Publication No. WO 01/32920, describes inhibitors, including certain ribozyme and antisense nucleic acid molecules, of specific genes, including cathepsin D, AEBP-1, stromelysin-3, cystatin B, protease inhibitor 1, sFRP4, gelsolin, IGFBP-3, dual specificity phosphatase 1, PAEP, Ig gamma chain, ferritin, complement component 3, pro- alpha- 1 type HI collagen, proline 4-hydroxylase, alpha-2 type I collagen, claudin-4, melanoma adhesion protein, procollagen C-endopeptidase enhancer, nascent-polypeptide-associated complex alpha polypeptide, elongation factor 1 alpha (EF-1-alpha). vitamin D3 25 hydroxylase, CSRP-1, steroidogenic acute regulatory protein, apolipoprotein E, transcobalamin IL prosaposin, early growth response 1 (EGR1), ribosomal protein S6, adenosine deaminase RNA-specific protein, RAD21, guanine nucleotide binding protein beta polypeptide 2-like 1 (RACKl) and podocalyxin genes which are all differentially expressed in tissues within individual patients with endometriosis.

Labarbera et al, International PCT Publication No. WO 00/73416, describes specific antisense nucleic acid molecules targeting follicle-stimulating hormone receptor. Storella et al, International PCT Publication No. WO 99/63116, describes modulators of Prothymosin gene products for treating endometriosis, including certain ribozymes and antisense nucleic acid molecules.

Summary Of The Invention

This invention features nucleic acid-based molecules, for example, enzymatic nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, triplex forming oligonucleotides, decoy RNA, dsRNA, siRNA, aptamers, and antisense nucleic acids containing nucleic acid cleaving chemical groups, and methods to modulate vascular endothelial growth factor (VEGF) and/or vascular endothelial growth factor receptor (VEGFr) gene expression. Non-limiting examples of genes that encode vascular endothelial growth factor receptors of the invention include VEGFRl, VEGFR2 or combinations thereof. In particular, the instant invention features nucleic acid-based molecules and methods that modulate the expression of vascular endothelial growth factor and/or vascular endothelial growth factor receptors, such as VEGFRl and/or VEGFR2, that are useful in preventing, treating, controlling, and/or diagnosing angiogenesis related diseases and conditions, including but not limited to tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and female reproductive disorders and conditions, including but not limited to endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), and menopausal dysfunction.

In one embodiment, the invention features one or more nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding vascular endothelial growth factor receptors. Specifically, the present invention features nucleic acid molecules that modulate the expression of VEGF (for example Genbank Accession No. NM_003376), VEGFRl receptor (for example Genbank Accession No. NM_002019), and VEGFR2 receptor (for example Genbank Accession No. NM_002253) that are useful in preventing, treating, controlling, and/or diagnosing tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and female reproductive disorders and conditions, including but not limited to endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), and menopausal dysfunction.

In one embodiment, the present invention features a compound having Formula I: (SEQ ID NO: 5977) 5' g_sa_sg_su_sugcUGAuGagg ccgaaa ggccGaaAgucugB 3'

wherein each a is 2'-O-methyl adenosine nucleotide, each g is a 2'-O-methyl guanosine nucleotide, each c is a 2'-O-methyl cytidine nucleotide, each u is a 2'-O-methyl uridine nucleotide, each A is adenosine, each G is guanosine, each s individually represents a phosphorothioate mternucleotide linkage, U is 2'-deoxy-2'-C-allyl uridine, and B is an inverted deoxyabasic moiety. This compound is also referred to as ANGIOZYME™ ribozyme.

In another embodiment, the present invention features a compound having Formula II: (SEQ ID NO: 5978).

5'-u_sa_sc_s a_sau ucU GAu Gag gcg aaa gcc Gaa Aag aca aB-3'

wherein each a is 2'-O-methyl adenosine nucleotide, each g is a 2'-O-methyl guanosine nucleotide, each c is a 2'-O-methyl cytidine nucleotide, each u is a 2'-O-methyl uridine nucleotide, each A is adenosine, each G is guanosine, each s individually represents a phosphorothioate internucleotide linkage, U is 2'-deoxy-2'-C-allyl uridine, and B is an inverted deoxyabasic moiety.

In one embodiment, the invention features a composition comprising a nucleic acid molecule of the invention in a pharmaceutically acceptable carrier. In another embodiment, the invention features a composition comprising a compound of Formula I and/or Formula II in a pharmaceutically acceptable carrier or diluent.

In one embodiment, the invention features a method of administering to a cell, for example a mammalian cell, including a human cell, a nucleic acid molecule of the invention comprising contacting the cell with the nucleic acid molecule under conditions suitable for administration, for example in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome. In another embodiment, the invention features a method of administering to a cell, for example a mammalian cell , including a human cell, a compound of Formula I and/or Formula Ilcomprising contacting the cell with the compound under conditions suitable for administration, for example in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.

In one embodiment, the present invention features a mammalian cell comprising a nucleic acid molecule of the invention, wherein the mammalian cell is, for example, a human cell. In another embodiment, the present invention also features a mammalian cell comprising the compound of Formula I and/or Formula U, wherein the mammalian cell is, for example, a human cell.

In one embodiment, the invention features a method of inhibiting angiogenesis, for example tumor angiogenesis, or ocular indications such as diabetic retinopathy, or age related macular degeneration, or endometrial neovascularization, in a subject comprising contacting the subject with a nucleic acid molecule of the invention, under conditions suitable for the inhibition. hi another embodiment, the invention features a method of inhibiting angiogenesis, for example tumor angiogenesis, or ocular indications such as diabetic retinopathy, or age related macular degeneration, or endometrial neovascularization, in a subject, comprising contacting the subject with a compound of Formula I and/or Formula II, under conditions suitable for the inhibition.

hi another embodiment, the invention features a method of treatment of a subjecthaving an ocular condition associated with the increased level of a VEGF receptor, for example diabetic retinopathy, or age related macular degeneration, comprising contacting cells of the subjectwith a nucleic acid molecule, such as an enzymatic nucleic acid molecule targeted against a VEGF receptor RNA, e.g., molecule according to Formula I and/or H, under conditions suitable for the treatment.

In another embodiment, the invention features a method of treatment of a subjecthaving a condition associated with an increased level of VEGR and/or a VEGF receptor, for example tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, ocular diseases or ocular indications such as diabetic retinopathy, or age related macular degeneration, rhuematoid arthritis, psoriasis endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), or menopausal dysfunction, comprising contacting cells of the subject with a nucleic acid molecule of the invention, such as a compound of Formula I and/or Formula H, under conditions suitable for the treatment.

In yet another embodiment, the inventive method of treatment further comprises the use of one or more drug therapies under conditions suitable for the treatment. Non-limiting examples of other drug therapies that can be used in combination with nucleic acid molecules of the invention include to 5-fluoro uridine, Leucovorin, Irinotecan (CAMPTOSAR® or CPT-11 or Camptothecin-11 or Campto), Paclitaxel, or Carboplatin, GnRH (gonadotropin releasing hormone) agonists, Lupron Depot (Leuprolide Acetate), Synarel (naferalin acetate), Zolodex (goserelin acetate), Suprefact (buserelin acetate), Danazol, or oral contraceptives including but not limited to Depo-Provera or Provera (medroxyprogesterone acetate), or any other estrogen/progesterone contraceptive.

hi one embodiment, the invention features a method of administering to a mammal, for example a human, a nucleic acid molecule of the invention comprising contacting the mammal with the nucleic acid molecule under conditions suitable for the administration, for example, in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome. In another embodiment, the invention features a method of administering to a mammal, for example a human, a compound of Formula I and/or Formula U comprising contacting the mammal with the compound under conditions suitable for the administration, for example, in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.

In one embodiment, the invention features a nucleic acid molecule which down regulates expression of a vascular endothelial growth factor (VEGF) and/or vascular endothelial growth factor receptor (VEGFr) gene, for example, wherein the VEGFr gene comprises VEGFRl or VEGFR2 and any combination thereof.

In one embodiment, a nucleic acid molecule of the invention, such as an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups, is adapted to treat, control and/or diagnose tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, ocular diseases or ocular indications, such as diabetic retinopathy, or age related macular degeneration, rhuematoid arthritis, psoriasis endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), or menopausal dysfunction.

Such nucleic acid molecules are also useful for the prevention of the diseases and conditions including diabetic retinopathy, macular degeneration, neovascular glaucoma, myopic degeneration, verruca vulgaris, angiofibroma of tuberous sclerosis, port-wine stains, Sturge Weber syndrome, Kippel-Trenaunay- Weber syndrome, Osier- Weber-Rendu syndrome and other diseases or conditions that are related to the levels of VEGFRl or VEGFR2 in a cell or tissue.

In another embodiment, the invention features a composition in a pharmaceutically acceptable carrier or diluent, comprising the nucleic acid molecule of the instant invention.

In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention is adapted for birth control.

hi one embodiment, an enzymatic nucleic acid molecule of the invention is in a hammerhead, friozyme, Zinzyme, DNAzyme, Amberzyme, or G-cleaver configuration.

i one embodiment, an enzymatic nucleic acid molecule of the invention comprises between 8 and 100 bases complementary to RNA of VEGFRl and/or VEGFR2 gene. In another embodiment, an enzymatic nucleic acid molecule of the invention comprises between 14 and 24 bases complementary to RNA of VEGFRl and/or VEGFR2 gene.

hi one embodiment, a siRNA molecule of the invention comprises a double stranded

RNA wherein one strand of the RNA is complementary to RNA of a VEGFRl and/or VEGFR2 gene. In another embodiment, a siRNA molecule of the invention comprises a double stranded RNA wherein one strand of the RNA comprises a portion of a sequence of RNA having a VEGFRl and/or VEGFR2 sequence, hi yet another embodiment, a siRNA molecule of the invention comprises a double stranded RNA wherein both strands of RNA are connected by a non-nucleotide linker. Alternately, a siRNA molecule of the invention comprises a double stranded RNA wherein both strands of RNA are connected by a nucleotide linker, such as a loop or stem loop structure.

In one embodiment, a single strand component of a siRNA molecule of the invention is from about 14 to about 50 nucleotides in length. In another embodiment, a single strand component of a siRNA molecule of the invention is about 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 nucleotides in length, hi yet another embodiment, a single strand component of a siRNA molecule of the invention is about 23 nucleotides in length. In one embodiment, a siRNA molecule of the invention is from about 28 to about 56 nucleotides in length, hi another embodiment, a siRNA molecule of the invention is about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 nucleotides in length. In yet another embodiment, a siRNA molecule of the invention is about 46 nucleotides in length. In one embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention is chemically synthesized.

In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention comprises at least one 2'-sugar modification.

In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5 A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing nucleic acid cleaving chemical groups of the invention comprises at least one nucleic acid base modification.

In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention comprises at least one phosphate backbone modification.

In one embodiment, the invention features a mammalian cell, for example a human cell, comprising a nucleic acid molecule of the invention.

In another embodiment, the invention features a method of reducing VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 expression or activity in a cell comprising contacting the cell with a nucleic acid molecule of the invention that modulates the expression and/or activity of VEGF and/or VEGFr, under conditions suitable for the reduction.

In another embodiment, a method of treatment of a subject having a condition associated with the level of VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 is featured, wherein the method further comprises the use of one or more drug therapies under conditions suitable for the treatment.

In one embodiment, the invention features a method for treatment of a subject having tumor angiogenesis, tumor angiogenesis, cancers including but not limited to tumor and cancer types shown under Diagnosis in Table III, ocular diseases or ocular indications such as diabetic retinopathy, or age related macular degeneration, rhuematoid arthritis, psoriasis and/or endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), or menopausal dysfunction, comprising administering to the subject a nucleic acid molecule of the invention that modulates the expression and/or activity of VEGF and/or VEGFr under conditions suitable for the treatment.

hi another embodiment, the invention features a method for birth control in a subject comprising administering to the subject a nucleic acid molecule of the invention that modulates the expression and/or activity of VEGF and/or VEGFr under conditions suitable for the treatment.

In another embodiment, the invention features a method of cleaving RNA encoded by a VEGF, VEGFRl and/or VEGFR2 gene comprising contacting an enzymatic nucleic acid molecule of the invention having endonuclease activity with RNA encoded by a VEGFRl and/or VEGFR2 gene under conditions suitable for the cleavage, for example, wherein the cleavage is carried out in the presence of a divalent cation, such as Mg2⁺.

In one embodiment, a nucleic acid molecule of the invention comprises a cap structure, for example a 3 ',3 '-linked or 5 ',5 '-linked deoxyabasic ribose derivative, wherein the cap structure is at the 5'-end, or 3 '-end, or both the 5'-end and the 3'-end of the enzymatic nucleic acid molecule.

In another embodiment, a nucleic acid molecule of the invention comprises a cap structure, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative, wherein the cap structure is at the 5'-end, or 3'-end, or both the 5'-end and the 3'-end of the antisense nucleic acid molecule.

In one embodiment, the invention features an expression vector comprising a nucleic acid sequence encoding at least one nucleic acid molecule of the invention such that the vector allows expression of the nucleic acid molecule.

In another embodiment, the invention features a mammalian cell, for example, a human cellcomprising an expression vector of the invention.

In yet another embodiment, an expression vector of the invention further comprises a sequence for a nucleic acid molecule complementary to RNA encoded by a VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 gene. hi one embodiment, an expression vector of the invention comprises a nucleic acid sequence encoding two or more nucleic acid molecules of the invention, which can be the same or different.

hi another embodiment, the invention features a method for treatment or control of tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and/or endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), or menopausal dysfunction, comprising administering to a subject a nucleic acid molecule of the invention that modulates the expression and/or activity of VEGF and/or VEGFr, such as an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention, under conditions suitable for the treatment, including administering to the subject one or more other therapies, for example, 5-fluoro uridine, Leucovorin, notecan (CAMPTOSAR® or CPT-11 or Camptothecin-11 or Campto), Paclitaxel, or Carboplatin.GnRH (gonadotropin releasing hormone) agonists, Lupron Depot (Leuprolide Acetate), Synarel (naferalin acetate), Zolodex (goserelin acetate), Suprefact (buserelin acetate), Danazol, or oral contraceptives including but not limited to Depo-Provera or Provera (medroxyprogesterone acetate), or any other estrogen/progesterone contraceptive.

In one embodiment, the method of treatment features a nucleic acid molecule of the invention, such as an enzymatic nucleic acid or antisense nucleic acid molecule, that comprises at least five ribose residues, at least ten 2'-0-methyl modifications, and a 3'- end modification, such as a 3 '-3' inverted abasic moiety. In another embodiment, a nucleic acid molecule of the invention further comprises phosphorothioate linkages on at least three of the 5' terminal nucleotides.

h another embodiment, the mvention features a method of administering to a mammal, for example a human, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2- 5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention, comprising contacting the mammal with the nucleic acid molecule under conditions suitable for the administration, for example, in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome. i yet another embodiment, the mvention features a method of administering to a mammal an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention in conjunction with other therapies, comprising contacting the mammal, for example a human, with the nucleic acid molecule and the other therapy under conditions suitable for the administration.

i another embodiment, other therapies contemplated by the instant invention that can be used in conjunction with the nucleic acid molecules of the instant invention include, but are not limited to, 5-fluoro uridine, Leucovorin, Irinotecan (CAMPTOSAR® or CPT-11 or Camptothecin-11 or Campto), Paclitaxel, or Carboplatin, GnRH (gonadotropin releasing hormone) agonists, Lupron Depot (Leuprolide Acetate), Synarel (naferalin acetate), Zolodex (goserelin acetate), Suprefact (buserelin acetate), Danazol, or oral contraceptives including but not limited to Depo-Provera or Provera (medroxyprogesterone acetate), or other estrogen/progesterone contraceptive.

In one embodiment, the invention features the use of an enzymatic nucleic acid molecule, to down-regulate the expression of VEGFRl and/or VEGFR2 genes in the treatment or control of tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and/or endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), or menopausal dysfunction. Such enzymatic nucleic acid molecule can be in the hammerhead, NCH, G-cleaver, Amberzyme, Zinzyme, and/or DNAzyme motif.

i another embodiment, the invention features the use of an enzymatic nucleic acid moleculeto down-regulate the expression of VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 genes, as a method of birth control. Such enzymatic nucleic acid molecule can be in the hammerhead, NCH, G-cleaver, Amberzyme, Zinzyme, and/or DNAzyme motif, hi one embodiment, the nucleic acid molecules of the invention have complementarity to the substrate. sequences in Tables V and VI. Examples of enzymatic nucleic acid molecules of the invention are shown in Tables V and VI. Examples of such enzymatic nucleic acid molecules consist essentially of sequences defined in these Tables.

By "inhibit", "down-regulate", or "reduce", it is meant that the expression of the gene, or level of nucleic acids or equivalent nucleic acids encoding one or more proteins or protein subunits, or activity of one or more proteins or protein subunits, such as VEGFRl, VEGFR2 and/or flk-1, is reduced below that observed in the absence of the nucleic acid molecules of the invention. In one embodiment, inhibition, down-regulation or reduction with enzymatic nucleic acid molecule preferably is below that level observed in the presence of an enzymatically inactive or attenuated molecule that is able to bind to the same site on the target nucleic acid, but is unable to cleave that nucleic acid, hi another embodiment, inhibition, down-regulation, or reduction with antisense oligonucleotides is preferably below that level observed in the presence of, for example, an oligonucleotide with scrambled sequence or with mismatches. In another embodiment, inhibition, down-regulation, or reduction of VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 with the nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence.

By "up-regulate" is meant that the expression of a gene, or level of nucleic acids or equivalent nucleic acids encoding one or more proteins or protein subunits, or activity of one or more proteins or protein subunits, such as VEGFRl and/or VEGFR2, is greater than that observed in the absence of the nucleic acid molecules of the invention. For example, the expression of a gene, such as VEGF and or VEGFr, such as VEGFRl and/or VEGFR2 gene, can be increased in order to treat, prevent, ameliorate, or modulate a pathological condition caused or exacerbated by an absence or low level of gene expression.

By "modulate" is meant that the expression of a gene, or level of nucleic acids or equivalent nucleic acids encoding one or more proteins or protein subunits, or activity of one or more proteins protein subunit(s) is up-regulated or down-regulated, such that the expression, level, or activity is greater than or less than that observed in the absence of the nucleic acid molecules of the invention.

By "enzymatic nucleic acid molecule" it is meant a nucleic acid molecule which has complementarity in a substrate binding region to a specified gene target, and also has an enzymatic activity which is active to specifically cleave a target nucleic acid. That is, the enzymatic nucleic acid molecule is able to intermolecularly cleave a nucleic acid and thereby inactivate a target nucleic acid molecule. These complementary regions allow sufficient hybridization of the enzymatic nucleic acid molecule to the target nucleic acid and thus permit cleavage. One hundred percent complementarity is preferred, but complementarity as low as 50-75%) can also be useful in this invention (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al, 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). The nucleic acids can be modified at the base, sugar, and/or phosphate groups. The term enzymatic nucleic acid is used interchangeably with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, aptazyme or aptamer-binding ribozyme, regulatable ribozyme, catalytic oligonucleotides, nucleozyme, DNAzyme, RNA enzyme, endoribonuclease, endonuclease, minizyme, leadzyme, oligozyme or DNA enzyme. All of these terminologies describe nucleic acid molecules with enzymatic activity. The specific enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving and/or ligation activity to the molecule (Cech et al, U.S. Patent No. 4,987,071; Cech et al, 1988, 260 JAMA 3030).

Several varieties of naturally-occurring enzymatic nucleic acids are known presently. Each can catalyze the hydrolysis of nucleic acid phosphodiester bonds in trans (and thus can cleave other nucleic acid molecules) under physiological conditions. Table I summarizes some of the characteristics of these ribozymes. In general, enzymatic nucleic acids act by first binding to a target nucleic acid. Such binding occurs through the target binding portion of a enzymatic nucleic acid which is held in close proximity to an enzymatic portion of the molecule that acts to cleave the target nucleic acid. Thus, the enzymatic nucleic acid first recognizes and then binds a target nucleic acid through complementary base-pairing, and once bound to the correct site, acts enzymatically to cut the target nucleic acid. Strategic cleavage of such a target nucleic acid will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its nucleic acid target, it is released from that nucleic acid to search for another target and can repeatedly bind and cleave new targets. Thus, a single ribozyme molecule is able to cleave many molecules of target nucleic acid, hi addition, the ribozyme is a highly specific inhibitor of gene expression, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target nucleic acid, but also on the mechanism of target nucleic acid cleavage. Single mismatches, or base-substitutions, near the site of cleavage can completely eliminate catalytic activity of a ribozyme.

In one embodiment of the inventions described herein, an enzymatic nucleic acid molecule of the invention is formed in a hammerhead or hairpin motif, but can also be formed in the motif of a hepatitis delta virus, group I intron, group II intron or RNase P RNA (in association with an RNA guide sequence), Neurospora VS RNA, DNAzymes, NCH cleaving motifs, or G-cleavers. Examples of such hammerhead motifs are described by Dreyfus, supra, Rossi et al, 1992, AIDS Research and Human Retroviruses 8, 183; of hairpin motifs by Hampel et al, EP0360257, Hampel and Tritz, 1989 Biochemistry 28, 4929, Feldstein et al, 1989, Gene 82, 53, Haseloff and Gerlach, 1989, Gene, 82, 43, and Hampel et al, 1990 Nucleic Acids Res. 18, 299; Chowrira & McSwiggen, US. Patent No. 5,631,359; an examples of a hepatitis delta virus motif is described by Perrotta and Been, 1992 Biochemistry 31, 16; examples of RNase P motifs are described by Guerrier-Takada et al, 1983 Cell 35, 849; Forster and Altman, 1990, Science 249, 783; Li and Airman, 1996, Nucleic Acids Res. 24, 835; examples of Neurospora VS RNA ribozyme motifs are described by Collins (Saville and Collins, 1990 Cell 61, 685-696; Saville and Collins, 1991 Proc. Natl. Acad. Sci. USA 88, 8826-8830; Collins and Olive, 1993 Biochemistry 32, 2795-2799; Guo and Collins, 1995, EMBO. J. 14, 363); examples of Group II introns are described by Griffin et al, 1995, Chem. Biol. 2, 761; Michels and Pyle, 1995, Biochemistry 34, 2965; Pyle et al, International PCT Publication No. WO 96/22689; an example of a Group I intron is described by_. Cech et al, U.S. Patent 4,987,071; and examples of DNAzymes are described by Usman et al, International PCT Publication No. WO 95/11304; Chartrand et al, 1995, NAR 23, 4092; Breaker et al, 1995, Chem. Bio. 2, 655; Santoro et al, 1997, PNAS 94, 4262, and Beigehnan et al, International PCT publication No. WO 99/55857. NCH cleaving motifs are described in Ludwig & Sproat, International PCT Publication No. WO 98/58058; and G-cleavers are described in Kore et al, 1998, Nucleic Acids Research 26, 4116-4120 and Eckstein et al, International PCT Publication No. WO 99/16871. Additional motifs such as the Aptazyme (Breaker et al, WO 98/43993), Amberzyme (Beigehnan et al, U.S. Serial No. 09/301,511) and Zinzyme (Figure 7) (Beigehnan et al, U.S. Serial No. 09/918,728), all included by reference herein including drawings, can also be used in the present invention. These specific motifs or configurations are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it have a specific substrate binding site which is complementary to one or more of the target gene RNA regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a RNA cleaving activity to the molecule (Cech et al, U.S. Patent No. 4,987,071).

By "nucleic acid molecule" as used herein is meant a molecule having nucleotides. The nucleic acid can be single, double, or multiple stranded and can comprise modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof.

By "enzymatic portion" or "catalytic domain" is meant that portion/region of a enzymatic nucleic acid molecule essential for cleavage of a nucleic acid substrate (for example see Figure 6). By "substrate binding arm" or "substrate binding domain" is meant that portion/region of a enzymatic nucleic acid which is able to interact, for example via complementarity (i.e., able to base-pair with), with a portion of its substrate. Preferably, such complementarity is 100%, but can be less if desired. For example, as few as 10 bases out of 14 can be base-paired (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al, 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). Examples of such arms are shown generally in Figures 6-8. That is, these arms contain sequences within a enzymatic nucleic acid which are intended to bring enzymatic nucleic acid and target nucleic acid together through complementary base-pairing interactions. An enzymatic nucleic acid of the invention can have binding arms that are contiguous or non-contiguous and can be of varying lengths. The length of the binding arm(s) are preferably greater than or equal to four nucleotides and of sufficient length to stably interact with the target nucleic acid; preferably 12-100 nucleotides; more preferably 14-24 nucleotides long (see for example Werner and Uhlenbeck, supra; Hamman et al, supra; Hampel et al, EP0360257; Berzal-Herranz et al, 1993, EMBO J., 12, 2567-73) or between 8 and 14 nucleotides long. If two binding arms are chosen, the design is such that the length of the binding arms are symmetrical (i.e., each of the binding arms is of the same length; e.g., four and four, five and five nucleotides, or six and six nucleotides, or seven and seven nucleotides long) or asymmetrical (i.e., the binding arms are of different length; e.g., three and five, six and three nucleotides; three and six nucleotides long; four and five nucleotides long; four and six nucleotides long; four and seven nucleotides long; and the like).

By "Inozyme" or "NCH" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as NCH Rz in Figure 6 and in Ludwig et al, International PCT Publication No. WO 98/58058 and US Patent Application Serial No. 08/878,640. Inozymes possess endonuclease activity to cleave nucleic acid substrates having a cleavage triplet NCH/, where N is a nucleotide, C is cytidine and H is adenosine, uridine or cytidine, and "/" represents the cleavage site. H is used interchangeably with X. Inozymes can also possess endonuclease activity to cleave nucleic acid substrates having a cleavage triplet NCN/, where N is a nucleotide, C is cytidine, and "/" represents the cleavage site. "F in Figure 6 represents an Inosine nucleotide, preferably a ribo-Inosine or xylo-Inosine nucleoside.

By "G-cleaver" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as G-cleaver Rz in Figure 6 and in Eckstein et al, US 6,127,173. G-cleavers possess endonuclease activity to cleave nucleic acid substrates having a cleavage triplet NYN/, where N is a nucleotide, Y is uridine or cytidine and "/" represents the cleavage site. G-cleavers can be chemically modified as is generally shown in Figure 6.

By "amberzyme" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described in Beigehnan et al, Intemational PCT publication No. WO 99/55857 and US Patent Application Serial No. 09/476,387. Amberzymes possess endonuclease activity to cleave nucleic acid substrates having a cleavage triplet NG/N, where N is a nucleotide, G is guanosine, and "/" represents the cleavage site. Amberzymes can be chemically modified to increase nuclease stability through substitutions using modified nucleotides. i addition, differing nucleoside and/or non- nucleoside linkers can be used to substitute the 5'-gaaa-3' loops shown in the figure. Amberzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2'-OH) group within its own nucleic acid sequence for activity.

By "zinzyme" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described in Figure 7 and in Beigehnan et al, International

PCT publication No. WO 99/55857 and US Patent Application Serial No. 09/918,728.

Zinzymes possess endonuclease activity to cleave nucleic acid substrates having a cleavage triplet including but not limited to YG/Y, where Y is uridine or cytidine, and G is guanosine and "/" represents the cleavage site. Zinzymes can be chemically modified to increase nuclease stability through substitutions as are generally shown in Figure 7, including substituting 2'-O-methyl guanosine nucleotides for guanosine nucleotides. In addition, differing nucleotide and/or non-nucleotide linkers can be used to substitute the 5'-gaaa-2' loop shown in the figure. Zinzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide (2'-OH) group within its own nucleic acid sequence for activity.

By 'DNAzyme' is meant, an enzymatic nucleic acid molecule that does not require the presence of a 2' -OH group within its own nucleic acid sequence for activity, hi particular embodiments the enzymatic nucleic acid molecule can have an attached linker or linkers or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2'-OH groups. DNAzymes can be synthesized chemically or expressed endogenously in vivo, by means of a single stranded DNA vector or equivalent thereof. An example of a DNAzyme is shown in Figure 8 and is generally reviewed in Usman et al, US patent No., 6,159,714; Chartrand et al, 1995, NAR 23, 4092; Breaker et al, 1995, Chem. Bio. 2, 655; Santoro et al, 1997, PNAS 94, 4262; Breaker, 1999, Nature Biotechnology, 17, 422-423; and Santoro et. al, 2000, J. Am. Chem. Soc, 122, 2433-39. The "10-23" DNAzyme motif is one particular type of DNAzyme that was evolved using in vitro selection, see Santoro et al, supra and as generally described in Joyce et al, US 5,807,718. Additional DNAzyme motifs can be selected for using techniques similar to those described in these references, and hence, are within the scope of the present invention.

By "sufficient length" is meant a nucleic acid molecule of the invention is long enough to provide the intended function under the expected condition. For example, a nucleic acid molecule of the invention needs to be of "sufficient length" to provide stable interaction with a target nucleic acid molecule under the expected binding conditions and environment. In another non-limiting example, for the binding arms of an enzymatic nucleic acid, "sufficient length" means that the binding arm sequence is long enough to provide stable binding to a target site under the expected reaction conditions and environment. The binding arms are not so long as to prevent useful turnover of the nucleic acid molecule.

By "stably interact" is meant interaction of an oligonucleotides with target nucleic acid (e.g., by forming hydrogen bonds with complementary nucleotides in the target under physiological conditions) that is sufficient to the intended purpose (e.g., cleavage of target nucleic acid by an enzyme).

By "equivalent" RNA to VEGF, VEGFRl and/or VEGFR2 is meant to include nucleic acid molecules having homology (partial or complete) to a nucleic acid encoding VEGF, VEGFRl and/or VEGFR2 proteins or encoding proteins with similar function as VEGF, VEGFRl and/or VEGFR2 proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites. The equivalent nucleic acid sequence also includes, in addition to the coding region, regions such as 5'- untranslated region, 3 '-untranslated region, introns, intron-exon junction and the like.

By "homology" is meant the nucleotide sequence of two or more nucleic acid molecules is partially or completely identical.

By "antisense nucleic acid", it is meant a non-enzymatic nucleic acid molecule that binds to target nucleic acid by means of RNA-RNA or RNA-DNA or RNA-PNA (protein nucleic acid; Eghol et al, 1993 Nature 365, 566) interactions and alters the activity of the target nucleic acid (for a review, see Stein and Cheng, 1993 Science 261, 1004 and Woolf et al, US patent No. 5,849,902). Typically, antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop. Thus, an antisense molecule can be complementary to two (or even more) noncontiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both. For a review of current antisense strategies, see Schmajuk et al, 1999, J. Biol. Chem., 274, 21783-21789, Delihas et al, 1997, Nature, 15, 751-753, Stein et al, 1997, Antisense N. A. Drug Dev., 7, 151, Crooke, 2000, Methods Enzymol, 313, 3-45; Crooke, 1998, Biotech. Genet. Eng. Rev., 15, 121-157, Crooke, 1997, Ad. Pharmacol, 40, 1-49. i addition, antisense DNA can be used to target nucleic acid by means of DNA-RNA interactions, thereby activating RNase H, which digests the target nucleic acid in the duplex. The antisense oligonucleotides can comprise one or more RNAse H activating region, which is capable of activating RNAse H cleavage of a target nucleic acid. Antisense DNA can be synthesized chemically or expressed via the use of a single stranded DNA expression vector or equivalent thereof.

By "RNase H activating region" is meant a region (generally greater than or equal to 4- 25 nucleotides in length, preferably from 5-11 nucleotides in length) of a nucleic acid molecule capable of binding to a target nucleic acid to form a non-covalent complex that is recognized by cellular RNase H enzyme (see for example Arrow et al, US 5,849,902; Arrow et al, US 5,989,912). The RNase H enzyme binds to a nucleic acid molecule-target nucleic acid complex and cleaves the target nucleic acid sequence. The RNase H activating region comprises, for example, phosphodiester, phosphorothioate (preferably at least four of the nucleotides are phosphorothiote substitutions; more specifically, 4-11 of the nucleotides are phosphorothiote substitutions); phosphorodithioate, 5'-thiophosphate, or methylphosphonate backbone chemistry or a combination thereof. In addition to one or more backbone chemistries described above, the RNase H activating region can also comprise a variety of sugar chemistries. For example, the RNase H activating region can comprise deoxyribose, arabino, fluoroarabino or a combination thereof, nucleotide sugar chemistry. Those skilled in the art will recognize that the foregoing are non-limiting examples and that any combination of phosphate, sugar and base chemistry of a nucleic acid that supports the activity of RNase H enzyme is within the scope of the definition of the RNase H activating region and the instant invention.

By "2-5A antisense chimera" is meant an antisense oligonucleotide containing a 5'- phosphorylated 2-5 '-linked adenylate residue. These chimeras bind to target nucleic acid in a sequence-specific manner and activate a cellular 2-5 A-dependent ribonuclease which, in turn, cleaves the target nucleic acid (Torrence et al, 1993 Proc. Natl. Acad. Sci. USA 90, 1300; Silverman et al, 2000, Methods Enzymol, 313, 522-533; Player and Torrence, 1998, Pharmacol. Ther., 78, 55-113).

By "triplex forming oligonucleotides" is meant an oligonucleotide that can bind to a double-stranded polynucleotide, such as DNA, in a sequence-specific manner to form a triple- strand helix. Formation of such triple helix structure has been shown to inhibit transcription of the targeted gene (Duval- Valentin et al, 1992 Proc. Natl. Acad. Sci. USA 89, 504; Fox, 2000, Curr. Med. Chem., 7, 17-37; Praseuth et. al, 2000, Biochim. Biophys. Ada, 1489, 181- 206).

By "gene" it is meant a nucleic acid that encodes an RNA, for example, nucleic acid sequences including but not limited to structural genes encoding a polypeptide.

The term "complementarity" as used herein refers to the ability of a nucleic acid to form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types, hi reference to nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., enzymatic nucleic acid cleavage, antisense or triple helix inhibition. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al, 1987, CSH Symp. Quant. Biol. LU pp.123-133; Frier et al, 1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al, 1987, J. Am. Chem. Soc. 109:3783-3785). A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule which can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary). "Perfectly complementary" means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.

By "RNA" is meant a molecule comprising at least one ribonucleotide residue. By "ribonucleotide" or "2'-OH" is meant a nucleotide with a hydroxyl group at the 2' position of a β-D-ribo-furanose moiety.

By "nucleic acid decoy molecule", or "decoy" as used herein is meant a nucleic acid molecule that mimics the natural binding domain for a ligand. The decoy therefore competes with the natural binding target for the binding of a specific ligand. For example, it has been shown that over-expression of HTV trans-activation response (TAR) RNA can act as a "decoy" and efficiently binds HIV tat protein, thereby preventing it from binding to TAR sequences encoded in the HIV RNA (Sullenger et al., 1990, Cell, 63, 601-608).

By "aptamer" or "nucleic acid aptamer" as used herein is meant a nucleic acid molecule that binds specifically to a target molecule wherein the nucleic acid molecule has sequence that is distinct from sequence recognized by the target molecule in its natural setting. Alternately, an aptamer can be a nucleic acid molecule that binds to a target molecule where the target molecule does not naturally bind to a nucleic acid. The target molecule can be any molecule of interest. For example, the aptamer can be used to bind to a ligand binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein. Similarly, the nucleic acid molecules of the instant invention can bind to VEGFRl or VEGFR2 receptors to block activity of the receptor. This is a non-limiting example and those in the art will reco nize that other embodiments can be readily generated using techniques generally known in the art, see for example Gold et al, US 5,475,096 and 5,270,163; Gold et al, 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J. Biotechnol, 74, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J. Biotechnol, 74, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628.

The term "double stranded RNA" or "dsRNA" as used herein refers to a double stranded RNA molecule capable of RNA interference "RNAi", including short interfering RNA "siRNA" see for example Bass, 2001, Nature, 411, 428-429; Elbashir et al., 2001, Nature, 411, 494-498; and Kreutzer et al, International PCT Publication No. WO 00/44895; Zernicka-Goetz et al, International PCT Publication No. WO 01/36646; Fire, International PCT Publication No. WO 99/32619; Plaetinck et al, International PCT Publication No. WO 00/01846; Mello and Fire, International PCT Publication No. WO 01/29058; Deschamps- Depaillette, International PCT Publication No. WO 99/07409; and Li et al, International PCT Publication No. WO 00/44914.

By "nucleic acid sensor molecule" or "allozyme" as used herein is meant a nucleic acid molecule comprising an enzymatic domain and a sensor domain, where the enzymatic nucleic acid domain's ability to catalyze a chemical reaction is dependent on the interaction with a target signaling molecule, such as a nucleic acid, polynucleotide, oligonucleotide, peptide, polypeptide, or protein, for example VEGF, VEGFRl and/or VEGFR2. The introduction of chemical modifications, additional functional groups, and/or linkers, to the nucleic acid sensor molecule can provide enhanced catalytic activity of the nucleic acid sensor molecule, increased binding affinity of the sensor domain to a target nucleic acid, and/or improved nuclease/chemical stability of the nucleic acid sensor molecule, and are hence within the scope of the present invention (see for example Usman et al, US Patent Application No. 09/877,526, George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al, International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al, US Patent Application Serial No. 09/205,520).

By "sensor component" or "sensor domain" of the nucleic acid sensor molecule as used herein is meant, a nucleic acid sequence (e.g., RNA or DNA or analogs thereof) which interacts with a target signaling molecule, for example a nucleic acid sequence in one or more regions of a target nucleic acid molecule or more than one target nucleic acid molecule, and which interaction causes the enzymatic nucleic acid component of the nucleic acid sensor molecule to either catalyze a reaction or stop catalyzing a reaction. In the presence of target signaling molecule of the invention, such as VEGF, VEGFRl and/or VEGFR2, the ability of the sensor component, for example, to modulate the catalytic activity of the nucleic acid sensor molecule, is inhibited or diminished. The sensor component can comprise recognition properties relating to chemical or physical signals capable of modulating the nucleic acid sensor molecule via chemical or physical changes to the structure of the nucleic acid sensor molecule. The sensor component can be derived from a naturally occurring nucleic acid binding sequence, for example, RNAs that bind to other nucleic acid sequences in vivo. Alternately, the sensor component can be derived from a nucleic acid molecule (aptamer) which is evolved to bind to a nucleic acid sequence within a target nucleic acid molecule (see for example Gold et al, US 5,475,096 and 5,270,163). The sensor component can be covalently linked to the nucleic acid sensor molecule, or can be non-covalently associated. A person skilled in the art will recognize that all that is required is that the sensor component is able to selectively inhibit the activity of the nucleic acid sensor molecule to catalyze a reaction.

By "target molecule" or "target signaling molecule" is meant a molecule capable of interacting with a nucleic acid sensor molecule, specifically a sensor domain of a nucleic acid sensor molecule, in a manner that causes the nucleic acid sensor molecule to be active or inactive. The interaction of the signaling agent with a nucleic acid sensor molecule can result in modification of the enzymatic nucleic acid component of the nucleic acid sensor molecule via chemical, physical, topological, or conformational changes to the structure of the molecule, such that the activity of the enzymatic nucleic acid component of the nucleic acid sensor molecule is modulated, for example is activated or deactivated. Signaling agents can comprise target signaling molecules such as macromolecules, ligands, small molecules, metals and ions, nucleic acid molecules including but not limited to RNA and DNA or analogs thereof, proteins, peptides, antibodies, polysaccharides, lipids, sugars, microbial or cellular metabolites, pharmaceuticals, and organic and inorganic molecules in a purified or unpurified form, for example VEGF, VEGFRl and or VEGFR2.

The term "triplex forming oligonucleotides" as used herein refers to an oligonucleotide that can bind to a double-stranded DNA in a sequence-specific manner to form a triple-strand helix. Formation of such a triple helix structure has been shown to inhibit transcription of a targeted gene (Duval-Valentin et al, 1992 Proc. Natl Acad. Sci. USA 89, 504; Fox, 2000, Curr. Med. Chem., 7, 17-37; Praseuth et. al, 2000, Biochim. Biophys. Ada, 1489, 181-206). The nucleic acid molecules that modulate the expression of VEGF and or VEGFr, such as VEGFRl and/or VEGFR2 specific nucleic acids, represent a novel therapeutic approach to treat or control a variety of angiogenesis related disorders and conditions, including but not limited to tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and/or endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), and/or menopausal dysfunction. The nucleic acid molecules that modulate the expression of VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 specific nucleic acids also represent a novel approach to control ovulation or embryonic implantation and therefore provide a novel means of birth control.

In one embodiment of the present invention, a nucleic acid molecule of the instant invention can be between 12 and 100 nucleotides in length. An exemplary enzymatic nucleic acid molecule of the invention is shown as Formula I and/or Formula π. For example, enzymatic nucleic acid molecules of the invention are preferably between 15 and 50 nucleotides in length, more preferably between 25 and 40 nucleotides in length, e.g., 34, 36, or 38 nucleotides in length (for example see Jarvis et al, 1996, J. Biol. Chem., 271, 29107- 29112). Exemplary DNAzymes of the invention are preferably between 15 and 40 nucleotides in length, more preferably between 25 and 35 nucleotides in length, e.g., 29, 30, 31, or 32 nucleotides in length (see for example Santoro et al, 1998, Biochemistry, 37, 13330-13342; Chartrand et al, 1995, Nucleic Acids Research, 23, 4092-4096). Exemplary antisense molecules of the invention are preferably between 15 and 75 nucleotides in length, more preferably between 20 and 35 nucleotides in length, e.g., 25, 26, 27, or 28 nucleotides in length (see for example Woolf et al, 1992, PNAS, 89, 7305-7309; Milner et al, 1997, Nature Biotechnology, 15, 537-541). Exemplary triplex forming oligonucleotide molecules of the invention are preferably between 10 and 40 nucleotides in length, more preferably between 12 and 25 nucleotides in length, e.g., 18, 19, 20, or 21 nucleotides in length (see for example Maher et al, 1990, Biochemistry, 29, 8820-8826; Srrobel and Dervan, 1990, Science, 249, 73-75). Those skilled in the art will recognize that all that is required is that the nucleic acid molecule be of length and conformation sufficient and suitable for the nucleic acid molecule to catalyze a reaction contemplated herein. The length of the nucleic acid molecules of the instant invention are not limiting within the general limits stated.

In a preferred embodiment, a nucleic acid molecule that modulates, for example, down-regulates, VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 replication or expression comprises between 8 and 100 bases complementary to a nucleic acid molecule of VEGFRl and/or VEGFR2. More preferably, a nucleic acid molecule that modulates VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 replication or expression comprises between 14 and 24 bases complementary to a nucleic acid molecule of VEGFRl and or VEGFR2.

The invention provides a method for producing a class of nucleic acid-based gene modulating agents which exhibit a high degree of specificity for the nucleic acid of a desired target. For example, a nucleic acid molecule of the invention is preferably targeted to a highly conserved sequence region of target nucleic acids encoding VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 (specifically VEGF, VEGFRl and/or VEGFR2 genes) such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules of the invention. Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required. Alternatively, the nucleic acid molecules can be expressed from DNA and/or RNA vectors that are delivered to specific cells.

As used in herein "cell" is used in its usual biological sense, and does not refer to an entire multicellular organism. The cell can, for example, be in vitro, e.g., in cell culture, or present in a multicellular organism, including,, e.g., birds, plants and mammals such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats. The cell may be prokaryotic

(e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell).

By "VEGFRl and/or VEGFR2 proteins" is meant, protein receptor or a mutant protein derivative thereof, having vascular endothelial growth factor receptor activity, for example, having the ability to bind vascular endothelial growth factor and/or having tyrosine kinase activity. By "highly conserved sequence region" is meant, a nucleotide sequence of one or more regions in a target gene does not vary significantly from one generation to the other or from one biological system to the other.

"Angiogenesis" refers to formation of new blood vessels which is an essential process in reproduction, development and wound repair. "Tumor angiogenesis" refers to the induction of the growth of blood vessels from surrounding tissue into a solid tumor. Tumor growth and tumor metastasis are dependent on angiogenesis (for a review see Folkman, 1985 supra; Folkman 1990 J. Natl. Cancer Inst., 82, 4; Folkman and Shing, 1992 J. Biol. Chem. 267, 10931).

Angiogenesis plays an important role in other diseases such as arthritis wherein new blood vessels have been shown to invade the joints and degrade cartilage (Folkman and Shing, supra).

"Retinopathy" refers to inflammation of the retina and or degenerative condition of the retina which may lead to occlusion of the retina and eventual blindness, h "diabetic retinopathy" angiogenesis causes the capillaries in the retina to invade the vitreous resulting in bleeding and blindness which is also seen in neonatal retinopathy (for a review see

Folkman, 1985 supra; Folkman 1990 supra; Folkman and Shing, 1992 supra).

Nucleic acid-based inhibitors of VEGF and/or VEGFr, such as VEGFRl and or VEGFR2, expression are useful for the prevention, treatment, and/or control of angiogenesis related disorders and conditions, including but not limited to, tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and/or endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), menopausal dysfunction, and other diseases or conditions that are related to or will respond to the levels of VEGF, VEGFRl and/or VEGFR2 in a cell or tissue, alone or in combination with other therapies. The reduction of VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 expression (specifically VEGF, VEGFRl and/or VEGFR2 gene RNA levels) and thus reduction in the level of the respective protein relieves, to some degree, the symptoms of the disease or condition. Nucleic acid-based inhibitors of VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 expression are also useful as birth control agents, for example by inhibition of ovulation or embryonic uterine implantation. The nucleic acid molecules of the invention can be added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues. The nucleic acid complexes can be locally admimstered to relevant tissues ex vivo, or in vivo through injection or infusion pump, with or without their incorporation in biopolymers. In preferred embodiments, the nucleic acid inhibitors comprise sequences, which are complementary to polynucleotides, for example DNA and RNA, having VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 sequence.

Triplex molecules of the invention can be provided targeted to DNA target regions, and containing the DNA equivalent of a target sequence or a sequence complementary to the specified target (substrate) sequence. Antisense molecules typically are complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop. Thus, the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both.

By "consists essentially of is meant that the active nucleic acid molecule of the invention, for example, an enzymatic nucleic acid molecule, contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind nucleic acid such that cleavage at the target site occurs. Other sequences can be present which do not interfere with such cleavage. Thus, a core region can, for example, include one or more loop, stem-loop structure, or linker which does not prevent enzymatic activity. Thus, a particular region of a nucleic acid molecule of the invention can be such a loop, stem-loop, nucleotide linker, and/or non-nucleotide linker and can be represented generally as sequence "X". Thus, a core region may, for example, include one or more loop or stem-loop structures which do not prevent enzymatic activity. For example, a core sequence for a hammerhead enzymatic nucleic acid can comprise a conserved sequence, such as 5'-CUGAUGAG-3' and 5'-CGAA- 3' connected by "X", where X is 5'-GCCGUUAGGC-3' (SEQ ID NO 5979), or any other Stem II region known in the art, or a nucleotide and/or non-nucleotide linker. Similarly, for other nucleic acid molecules of the instant invention, such as Inozyme, G-cleaver, amberzyme, zinzyme, DNAzyme, antisense, 2-5A antisense, triplex forming nucleic acid, aptamers, decoy nucleic acids, dsRNA or siRNA, other sequences or non-nucleotide linkers can be present that do not interfere with the function of the nucleic acid molecule. Sequence X can be a linker of ≥ 2 nucleotides in length, preferably 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 26, 30, where the nucleotides can preferably be internally base-paired to form a stem of preferably > 2 base pairs. Alternatively or in addition, sequence X can be a non-nucleotide linker, hi yet another embodiment, the nucleotide linker X can be a nucleic acid aptamer, such as an ATP aptamer, HTV Rev aptamer (RRE), HIV Tat aptamer (TAR) and others (for a review see Gold et al, 1995, Annu. Rev. Biochem., 64, 763; and Szostak & Ellington, 1993, in The RNA World, ed. Gesteland and Atkins, pp. 511, CSH Laboratory Press). A nucleic acid aptamer includes a nucleic acid sequence capable of interacting with a ligand. The ligand can be any natural or a synthetic molecule, including but not limited to a resin, metabolites, nucleosides, nucleotides, drugs, toxins, transition state analogs, peptides, lipids, proteins, amino acids, nucleic acid molecules, hormones, carbohydrates, receptors, cells, viruses, bacteria and others.

In yet another embodiment, the non-nucleotide linker X is as defined herein. The tenn "non-nucleotide" as used herein include either abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, or polyhydrocarbon compounds. Specific examples include those described by Seela and Kaiser, Nucleic Acids Res. 1990, 7<°:6353 and Nucleic Acids Res. 1987, 75:3113; Cload and Schepartz, J. Am. Chem. Soc. 1991, 773:6324; Richardson and Schepartz, J Am. Chem. Soc. 1991, 775:5109; Ma et al, Nucleic Acids Res. 1993, 27:2585 and Biochemistry 1993, 32:1751; Durand et al, Nucleic Acids Res. 1990, 75:6353; McCurdy et al, Nucleosides & Nucleotides 1991, 70:287; Jschke et al, Tetrahedron Lett. 1993, 34:301; Ono et al, Biochemistry 1991, 30:9914; Arnold et al, International Publication No. WO 89/02439; Usman et al, International Publication No. WO 95/06731; Dudycz et al, International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc. 1991, 773:4000, all hereby incorporated by reference herein.

A "non-nucleotide" further means any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound can be abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine. Thus, in one embodiment, the invention features an enzymatic nucleic acid molecule having one or more non-nucleotide moieties, and having enzymatic activity to cleave an RNA or DNA molecule.

In another aspect of the invention, nucleic acid molecules that interact with target nucleic acid molecules and down-regulate VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 (specifically VEGF, VEGFRl and/or VEGFR2 gene) activity are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Enzymatic nucleic acid molecule or antisense expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. The recombinant vectors capable of expressing the enzymatic nucleic acid molecules or antisense are delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of enzymatic nucleic acid molecules or antisense. Such vectors can be repeatedly administered as necessary. Once expressed, the enzymatic nucleic acid molecules or antisense bind to the target nucleic acid and down-regulate its function or expression. Delivery of enzymatic nucleic acid molecule or antisense expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex- planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector.

By "vectors" is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.

By "subject" or "patient" is meant an organism, which is a donor or recipient of explanted cells, or the cells themselves. "Subject" or "Patient" also refers to an organism to which the nucleic acid molecules of the invention can be admimstered. Preferably, a subject or patient is a mammal or mammalian cells. More preferably, a subject or patient is a human or human cells.

By "enhanced enzymatic activity" is meant to include activity measured in cells and/or in vivo where the activity is a reflection of both the catalytic activity and the stability of the nucleic acid molecules of the invention. In this invention, the product of these properties can be increased in vivo compared to an all RNA enzymatic nucleic acid or all DNA enzyme, i some cases, the activity or stability of the nucleic acid molecule can be decreased (i.e., less than ten-fold), but the overall activity of the nucleic acid molecule is enhanced, in vivo.

The nucleic acid molecules of the instant invention, individually, or in combination or in conjunction with other drugs, can be used to treat diseases or conditions discussed above. For example, to treat a disease or condition associated with the levels of VEGFRl and/or VEGFR2, the patient can be treated, or other appropriate cells can be treated, as is evident to those skilled in the art, individually or in combination with one or more drugs under conditions suitable for the treatment. In a further embodiment, the described molecules of the invention can be used in combination with other known treatments to treat conditions or diseases discussed above. For example, the described molecules can be used in combination with one or more known therapeutic agents to treat angiogenesis related disorders and conditions, including but not limited to tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and/or endometriosis, birth control, endometrial tumors, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), menopausal dysfunction, endometrial carcinoma, and/or other diseases or conditions which respond to the modulation of VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 expression.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.

Brief Description of the Drawings

Figure 1 shows a secondary structure model of ANGIOZYME™ ribozyme bound to its RNA target.

Figure 2 shows a time course of inhibition of primary tumor growth following systemic administration of ANGIOZYME™ in the LLC mouse model.

Figure 3 shows inhibition of primary tumor growth following systemic administration of ANGIOZYME™ according to a certain dosing regimen in the LLC mouse model.

Figure 4 shows a dose-dependent inhibition of tumor metastases following systemic administration of ANGIOZYME™ in a mouse colorectal model.

Figure 5 is a graph showing the plasma concentration profile of ANGIOZYME™ after a single subcutaneous (SC) dose of 10, 30, 100 or 300 mgm².

Figure 6 shows examples of chemically stabilized ribozyme motifs. HH Rz, represents hammerhead ribozyme motif (Usman et al, 1996, Curr. Op. Struct. Bio., 1, 527); NCH Rz represents the NCH ribozyme motif (Ludwig et al, International PCT Publication No. WO

98/58058 and US Patent Application Serial No. 08/878,640); G-CIeaver, represents G- cleaver ribozyme motif (Kore et al, 1998, Nucleic Acids Research 26, 4116-4120, Eckstein et al, US 6,127,173). N or n, represent independently a nucleotide which can be same or different and have complementarity to each other; rl, represents ribo-Inosine nucleotide; arrow indicates the site of cleavage within the target. Position 4 of the HH Rz and the NCH Rz is shown as having 2'-C-allyl modification, but those skilled in the art will recognize that this position can be modified with other modifications well known in the art, so long as such modifications do not significantly inhibit the activity of the ribozyme.

Figure 7 shows an example of a Zinzyme A ribozyme motif that is chemically stabilized (see for example Beigehnan et al, International PCT publication No. WO 99/55857 and US Patent Application Serial No. 09/918,728).

Figure 8 shows an example of a DNAzyme motif described by Santoro et al, 1997,

PNAS, 94, 4262 and Joyce et al, US 5,807,718 .

Figure 9 shows data demonstrating the inhibition of soluble VEGFRl in a clinical study using ANGIOZYME (SEQ ID NO: 5977) .

Figure 10 shows an generalized outline for the mouse model of proliferative retinopathy showing the points of ribozyme administration.

Figure 11 shows a graph demonstrating the efficacy of a VEGF-receptor-targeted enzymatic nucleic acid molecule in a mouse model of proliferative retinopathy.

Detailed Description of the Invention

Nucleic Acid Molecules and Mechanism of Action Enzymatic Nucleic Acid: Several varieties of naturally-occurring enzymatic nucleic acids are presently known. Pn addition, several in vitro selection (evolution) strategies (Orgel, 1979, Proc. R. Soc. London, B 205, 435) have been used to evolve new nucleic acid catalysts capable of catalyzing cleavage and ligation of phosphodiester linkages (Joyce, 1989, Gene, 82, 83-87; Beaudry et al, 1992, Science 257, 635-641; Joyce, 1992, Scientific American 267, 90-97; Breaker et al, 1994, TIBTECH 12, 268; Bartel et α/.,1993, Science 261:1411-1418; Szostak, 1993, TIBS 17, 89-93; Kumar et al, 1995, FASEB J., 9, 1183; Breaker, 1996, Curr. Op. Biotech., 7, 442; Santoro et al, 1997, Proc. Natl. Acad. Sci., 94, 4262; Tang et al, 1997, RNA 3, 914; Nakamaye & Eckstein, 1994, supra; Long & Uhlenbeck, 1994, supra; Ishizaka et al, 1995, supra; Vaish et al, 1997, Biochemistry 36, 6495; all of these are incorporated by reference herein). Each can catalyze a series of reactions including the hydrolysis of phosphodiester bonds in trans (and thus can cleave other nucleic acid molecules) under physiological conditions.

The enzymatic nature of an enzymatic nucleic acid molecule has significant advantages, one advantage being that the concentration of enzymatic nucleic acid molecule necessary to affect a therapeutic treatment is lower. This advantage reflects the ability of the enzymatic nucleic acid molecule to act enzymatically. Thus, a single enzymatic nucleic acid molecule is able to cleave many molecules of target nucleic acid. In addition, the enzymatic nucleic acid molecule is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target nucleic acid , but also on the mechanism of target nucleic acid cleavage. Single mismatches, or base- substitutions, near the site of cleavage can be chosen to completely eliminate catalytic activity of a enzymatic nucleic acid molecule.

Nucleic acid molecules having an endonuclease enzymatic activity are able to repeatedly cleave other separate nucleic acid molecules in a nucleotide base sequence-specific manner. With the proper design, such enzymatic nucleic acid molecules can be targeted to RNA transcripts, and achieve efficient cleavage in vitro (Zaug et al, 324, Nature 429 1986; Uhlenbeck, 1987 Nature 328, 596; Kim et al, 84 Proc. Natl. Acad. Sci. USA 8788, 1987; Dreyfus, 1988, Einstein Quart. J. Bio. Med., 6, 92; Haseloff and Gerlach, 334 Nature 585, 1988; Cech, 260 JAMA 3030, 1988; and Jefferies et al, 17 Nucleic Acids Research 1371, 1989; Santoro et al, 1997 supra).

Because of their sequence specificity, trans-cleaving enzymatic nucleic acid molecules can be used as therapeutic agents for human disease (Usman & McSwiggen, 1995 Ann. Rep. Med. Chem. 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem. 38, 2023-2037). Enzymatic nucleic acid molecules can be designed to cleave specific nucleic acid targets within the background of cellular nucleic acid. Such a cleavage event renders the nucleic acid non-functional and abrogates protein expression from that nucleic acid. In this manner, synthesis of a protein associated with a disease state can be selectively inhibited (Warashina et al, 1999, Chemistry and Biology, 6, 237-250).

Enzymatic nucleic acid molecules of the invention that are allosterically regulated ("allozymes") can be used to down-regulate VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2, expression. These allosteric enzymatic nucleic acids or allozymes (see for example Usman et al, US Patent Application No. 09/877,526, George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al, International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al, US Patent Application Serial No. 09/205,520) are designed to respond to a signaling agent, for example, mutant VEGFRl and/or VEGFR2 protein, wild-type VEGFRl and/or VEGFR2 protein, mutant VEGFRl and/or VEGFR2 RNA, wild-type VEGFRl and/or VEGFR2 RNA, other proteins and/or RNAs involved in VEGF signal transduction, compounds, metals, polymers, molecules and/or drugs that are targeted to VEGFRl and/or VEGFR2 expression, which in turn modulates the activity of the enzymatic nucleic acid molecule. In response to interaction with a predetermined signaling agent, the activity of the allosteric enzymatic nucleic acid is activated or inhibited such that the expression of a particular target is selectively down-regulated. The target can comprise wild-type VEGFRl and/or VEGFR2, mutant VEGFRl and/or VEGFR2, and/or a predetermined component of the VEGF signal transduction pathway, hi a specific example, allosteric enzymatic nucleic acid molecules that are activated by interaction with a RNA encoding VEGF protein are used as therapeutic agents in vivo. The presence of RNA encoding the VEGF protein activates the allosteric enzymatic nucleic acid molecule that subsequently cleaves the RNA encoding a VEGFRl and/or VEGFR2 protein resulting in the inhibition of VEGFRl and/or VEGFR2 protein expression.

In another non-limiting example, an allozyme can be activated by a VEGF and or VEGFr, such as VEGFRl and/or VEGFR2 protein, peptide, or mutant polypeptide that causes the allozyme to inhibit the expression of VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 genes, by, for example, cleaving RNA encoded by VEGF, VEGFRl and/or VEGFR2 gene, hi this non-limiting example, the allozyme acts as a decoy to inhibit the function of VEGF, VEGFRl and/or VEGFR2 and also inhibit the expression of VEGF, VEGFRl and/or VEGFR2 once activated by the VEGF, VEGFRl and/or VEGFR2 protein.

Antisense: Antisense molecules can be modified or unmodified RNA, DNA, or mixed polymer oligonucleotides and primarily function by specifically binding to matching sequences resulting in inhibition of peptide synthesis (Wu-Pong, Nov 1994, BioPharm, 20- 33). The antisense oligonucleotide binds to target RNA by Watson Crick base-pairing and blocks gene expression by preventing ribosomal translation of the bound sequences either by steric blocking or by activating RNase H enzyme. Antisense molecules can also alter protein synthesis by interfering with RNA processing or transport from the nucleus into the cytoplasm (Mukhopadhyay & Roth, 1996, Crit. Rev. in Oncogenesis 7, 151-190).

In addition, binding of single stranded DNA to RNA can result in nuclease degradation of the heteroduplex (Wu-Pong, supra; Crooke, supra). To date, the only backbone modified DNA chemistry which act as substrates for RNase H are phosphorothioates, phosphorodithioates, and borontrifluoridates. Recently it has been reported that 2'-arabino and 2 '-fluoro arabino- containing oligos can also activate RNase H activity.

A number of antisense molecules have been described that utilize novel configurations of chemically modified nucleotides, secondary structure, and/or RNase H substrate domains (Woolf et al, International PCT Publication No. WO 98/13526; Thompson et al, International PCT Publication No. WO 99/54459; Hartmann et al, USSN 60/101,174 which was filed on September 21, 1998) all of these are incorporated by reference herein in their entirety.

hi addition, antisense deoxyoligoribonucleotides can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector or equivalents and variations thereof.

Triplex Forming Oligonucleotides (TFO): Single stranded DNA can be designed to bind to genomic DNA in a sequence specific manner. TFOs are comprised of pyrimidine-rich oligonucleotides which bind DNA helices through Hoogsteen Base-pairing (Wu-Pong, supra). The resulting triple helix composed of the DNA sense, DNA antisense, and TFO disrupts RNA synthesis by RNA polymerase. The TFO mechanism can result in gene expression or cell death since binding can be irreversible (Mukhopadhyay & Roth, supra). 2-5A Antisense Chimera: The 2-5A system is an interferon mediated mechanism for

RNA degradation found in higher vertebrates (Mitra et al, 1996, Proc Nat Acad Sci USA 93, 6780-6785). Two types of enzymes, 2-5A synthetase and RNase L, are required for RNA cleavage. The 2-5A synthetases require double stranded RNA to form 2'-5' oligoadenylates (2-5 A). 2-5 A then acts as an allosteric effector for utilizing RNase L which has the ability to cleave single stranded RNA. The ability to form 2-5A structures with double stranded RNA makes this system particularly useful for inhibition of viral replication.

(2'-5') oligoadenylate structures can be covalently linked to antisense molecules to form chimeric oligonucleotides capable of RNA cleavage (Torrence, supra). These molecules putatively bind and activate a 2-5A dependent RNase, the oligonucleotide/enzyme complex then binds to a target RNA molecule which can then be cleaved by the RNase enzyme. RNAi: Double-stranded RNAs can suppress expression of homologous genes through an evolutionarily conserved process named RNA interference (RNAi) or post-transcriptional gene silencing (PTGS). One mechanism underlying silencing is the degradation of target mRNAs by an RNP complex, which contains short interfering RNAs (siRNAs) as guides to substrate selection. Short interfering RNAs are typically 21 to 23 nucleotides in length. A bidentate nuclease called Dicer has been implicated as the protein responsible for siRNA production. For example, a double-stranded RNA (dsRNA) matching a gene sequence is synthesized in vitro and introduced into a cell. The dsRNA feeds into a biological pathway and is broken into short pieces of short interfering (si) RNAs. With the help of cellular enzymes such as Dicer, the siRNA triggers the degradation of the messenger RNA that matches its sequence (see for example Tuschl et al, International PCT Publication No. WO 01/75164; Bass, 2001, Nature, 411, 428-429; Elbasbir et al., 2001, Nature, 411, 494-498; and Kreutzer et al, International PCT Publication No. WO 00/44895).

Target sites Targets for useful nucleic acid molecules of the invention, such as enzymatic nucleic acid molecules, dsRNA, and antisense nucleic acids can be determined as disclosed in Draper et al, WO 93/23569; Sullivan et al, WO 93/23057; Thompson et al, WO 94/02595; Draper et al, WO 95/04818; McSwiggen et al, US Patent No. 5,525,468, and hereby incorporated by reference herein in totality. Other examples include the following PCT applications, which concern inactivation of expression of disease-related genes: WO 95/23225, WO 95/13380, WO 94/02595, incorporated by reference herein. Rather than repeat the guidance provided in those documents here, below are provided specific examples of such methods, not limiting to those in the art. Enzymatic nucleic acid molecules and antisense to such targets are designed as described in those applications and synthesized to be tested in vitro and in vivo, as also described. The sequences of human VEGF, VEGFRl and/or VEGFR2 RNAs are screened for optimal nucleic acid target sites using a computer-folding algorithm. Potential nucleic acid binding cleavage sites are identified. While human sequences can be screened and nucleic acid molecules thereafter designed, as discussed in Stinchcomb et al, WO 95/23225, mouse targeted enzymatic nucleic acid molecules can be useful to test efficacy of action of the nucleic acid molecule prior to testing in humans.

Nucleic acid molecule binding/cleavage sites are identified, for example enzymatic nucleic acid, antisense, and dsRNA mediated binding sites are chosen. For enzymatic nucleic acid molecules of the invention, the nucleic acid molecules are individually analyzed by computer folding (Jaeger et al, 1989 Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the sequences fold into the appropriate secondary structure. Those nucleic acid molecules with unfavorable intramolecular interactions such as between the binding arms and the catalytic core can be eliminated from consideration. Varying binding arm lengths can be chosen to optimize activity.

Nucleic acids, such as antisense, RNAi, and/or enzymatic nucleic acid molecule binding/cleavage sites are identified and are designed to anneal to various sites in the nucleic acid target. The binding arms of enzymatic nucleic acid molecules of the invention are complementary to the target site sequences described above. Antisense and RNAi sequences are designed to have partial or complete complementarity to the nucleic acid target. The nucleic acid molecules can be chemically synthesized. The method of synthesis used follows the procedure for normal DNA/RNA synthesis as described below and in Usman et al, 1987 J. Am. Chem. Soc, 109, 7845; Scaringe et al, 1990 Nucleic Acids Res., 18, 5433; and Wincott et al, 1995 Nucleic Acids Res. 23, 2677-2684; Caruthers et al, 1992, Methods in Enzymology 211,3-19. Synthesis of Nucleic acid Molecules

Synthesis of nucleic acids greater than 100 nucleotides in length is difficult using automated methods, and the therapeutic cost of such molecules is prohibitive. In this invention, small nucleic acid motifs ("small refers to nucleic acid motifs less than about 100 nucleotides in length, preferably less than about 80 nucleotides in length, and more preferably less than about 50 nucleotides in length; e.g., antisense oligonucleotides, enzymatic nucleic acids, aptamers, allozymes, decoys, siRNA etc.) are preferably used for exogenous delivery. The simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA structure. Exemplary molecules of the instant invention are chemically synthesized, and others can similarly be synthesized.

DNA Oligonucleotides are synthesized using protocols known in the art as described in

Caruthers et al, 1992, Methods in Enzymology 211, 3-19, Thompson et al, International PCT Publication No. WO 99/54459, Wincott et al, 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al, 1997, Methods Mol Bio., 74, 59, Brennan et al, 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, US patent No. 6,001,311. All of these references are incorporated herein by reference. The synthesis of oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'- end. hi a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, hie. synthesizer using a 0.2 μmol scale protocol with a 2.5 min coupling step for 2'-O-methylated nucleotides and a 45 sec coupling step for 2'-deoxy nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be performed on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, CA) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M = 6.6 μmol) of 2'-O-methyl phosphoramidite and a 105-fold excess of S-ethyl tetrazole (60 μL of 0.25 M = 15 μmol) can be used in each coupling cycle of 2'-O-methyl residues relative to polymer-bound 5'- hydroxyl. A 22-fold excess (40 μL of 0.11 M = 4.4 μmol) of deoxy phosphoramidite and a 70-fold excess of S-ethyl tetrazole (40 μL of 0.25 M = 10 μmol) can be used in each coupling cycle of deoxy residues relative to polymer-bound 5 '-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, ie. synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/ 10% 2,6-lutidine in THF (ABI); and oxidation solution is 16.9 mM I₂, 49 mM pyridine, 9% water in THF (PERSEPTIVE™). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, hie. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2- Benzodithiol-3-one 1,1-dioxide, 0.05 M in acetonitrile) is used.

Deprotection of the DΝA polynucleotides is performed as follows: the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 °C for 10 min. After cooling to -20 °C, the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCΝ:H2O/3:l:l, vortexed and the supernatant is then added to the first supernatant. The combined supematants, containing the oligoribonucleotide, are dried to a white powder.

The method of synthesis used for RNA oligonucleotides including certain nucleic acid molecules of the invention follows the procedure as described in Usman et al, 1987, J. Am. Chem. Soc, 109, 7845; Scaringe et al, 1990, Nucleic Acids Res., 18, 5433; and Wincott et al, 1995, Nucleic Acids Res. 23, 2677-2684 Wincott et al, 1997, Methods Mol. Bio. , 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. hi a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a 2.5 min coupling step for 2'-O-methylated nucleotides. Table II outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be done on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, CA) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M = 6.6 μmol) of 2'-O-methyl phosphoramidite and a 75-fold excess of S-ethyl tetrazole (60 μL of 0.25 M = 15 μmol) can be used in each coupling cycle of 2'-O-methyl residues relative to polymer-bound 5'-hydroxyl. A 66-fold excess (120 μL of 0.11 M = 13.2 μmol) of alkylsilyl (ribo) protected phosphoramidite and a 150-fold excess of S-ethyl tetrazole (120 μL of 0.25 M = 30 μmol) can be used in each coupling cycle of ribo residues relative to polymer-bound 5 '-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution is 16.9 mM I₂, 49 mM pyridine, 9% water in THF (PERSEPTTVΕ™). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American Intemational Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-l,2-Benzodithiol-3-one 1,1- dioxideθ.05 M in acetonitrile) is used.

Deprotection of the RΝA is performed using either a two-pot or one-pot protocol. For the two-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 °C for 10 min. After cooling to -20 °C, the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCΝ:H2O/3:l:l, vortexed and the supernatant is then added to the first supernatant. The combined supematants, containing the oligoribonucleotide, are dried to a white powder. The base deprotected oligoribonucleotide is resuspended in anhydrous TEA/HF/NMP solution (300 μL of a solution of 1.5 mL N- methylpyrrolidinone, 750 μL TEA and 1 mL TEA^»3HF to provide a 1.4 M HF concentration) and heated to 65 °C. After 1.5 h, the oligomer is quenched with 1.5 M NH4HCO3.

Alternatively, for the one-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO: 1/1 (0.8 mL) at 65 °C for 15 min. The vial is brought to r.t. TEA»3HF

(0.1 mL) is added and the vial is heated at 65 °C for 15 min. The sample is cooled at -20 °C and then quenched with 1.5 M NH4HCO3. For purification of the trityl-on oligomers, the quenched NH₄HCO₃ solution is loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing the loaded cartridge with water, the RNA is detritylated with 0.5% TFA for 13 min. The cartridge is then washed again with water, salt exchanged with 1 M NaCl and washed with water again. The oligonucleotide is then eluted with 30% acetonitrile.

Inactive hammerhead ribozymes or binding attenuated control (BAC) oligonucleotides) are synthesized by substituting a U for G5 and a U for A14 (numbering from Hertel, K. J., et al, 1992, Nucleic Acids Res., 20, 3252). Similarly, one or more nucleotide substitutions can be introduced in otlier enzymatic nucleic acid molecules to inactivate the molecule and such molecules can serve as a negative control.

The average stepwise coupling yields are typically >98% (Wincott et al, 1995 Nucleic

Acids Res. 23, 2677-2684). Those of ordinary skill in the art will recognize that the scale of synthesis can be adapted to be larger or smaller than the example described above including but not Umited to 96 well format, all that is important is the ratio of chemicals used in the reaction.

Alternatively, the nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example by ligation (Moore et al, 1992,

Science 256, 9923; Draper et al, International PCT publication No. WO 93/23569; Shabarova et al, 1991, Nucleic Acids Research 19, 4247; Bellon et al, 1997, Nucleosides &

Nucleotides, 16, 951; Bellon etal, 1997, Bioconjugate Chem. 8, 204).

Preferably, the nucleic acid molecules of the present invention are modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2'-amino, 2'- C-allyl, 2'-flouro, 2'-0-methyl, 2'-H (for a review see Usman and Cedergren, 1992, TIBS 17, 34; Usman et al, 1994, Nucleic Acids Symp. Ser. 31, 163). Ribozymes are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, Supra, the totality of which is hereby incorporated herein by reference) and are re-suspended in water.

Optimizing Activity of the nucleic acid molecule of the invention. Chemically synthesizing nucleic acid molecules with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases can increase their potency (see e.g., Eckstein et al, International Publication No. WO 92/07065; Perrault et al, 1990 Nature 344, 565; Pieken et al., 1991, Science 253, 314; Usman and Cedergren, 1992, Trends in Biochem. Sci. 17, 334; Usman et al, Intemational Publication No. WO 93/15187; and Rossi et al, International Publication No. WO 91/03162; Sproat, US Patent No. 5,334,711; Gold et al, US 6,300,074; and Burgin et al, supra; all of which are incorporated by reference herein). Modifications which enhance their efficacy in cells, and removal of bases from nucleic acid molecules to shorten oligonucleotide synthesis times and reduce chemical requirements are desired. (All these publications are hereby incorporated by reference herein).

There are several examples in the art describing sugar, base and phosphate modifications that can be introduced into nucleic acid molecules with significant enhancement in their nuclease stability and efficacy. For example, oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'-flouro, 2'-O-methyl, 2'-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992, TIBS. 17, 34; Usman et al, 1994, Nucleic Acids Symp. Ser. 31, 163; Burgin et al, 1996, Biochemistry, 35, 14090). Sugar modification of nucleic acid molecules have been extensively described in the art (see Eckstein et al, International Publication PCT No. WO 92/07065; Perrault et al. Nature, 1990, 344, 565-568; Pieken et al. Science, 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem. Sci. , 1992, 17, 334-339; Usman et al. International Publication PCT No. WO 93/15187; Sproat, US Patent No. 5,334,711 and Beigehnan et al, 1995, J. Biol. Chem., 270, 25702; Beigehnan et al, Intemational PCT publication No. WO 97/26270; Beigehnan et al, US Patent No. 5,716,824; Usman et al, US patent No. 5,627,053; Woolf et al, Intemational PCT Publication No. WO 98/13526; Thompson et al, USSN 60/082,404 which was filed on April 20, 1998; Karpeisky et al, 1998, Tetrahedron Lett., 39, 1131; Earnshaw and Gait, 1998, Biopolymers (Nucleic acid Sciences), 48, 39-55; Verma and Eckstein, 1998, Annu. Rev. Biochem., 67, 99-134; and Burlina et al, 1997, Bioorg. Med. Chem., 5, 1999-2010; all of the references are hereby incorporated in their totality by reference herein). Such publications describe general methods and strategies to determine the location of incorporation of sugar, base and/or phosphate modifications and the like into ribozymes without inhibiting catalysis, and are incorporated by reference herein. In view of such teachings, similar modifications can be used as described herein to modify the nucleic acid molecules of the instant invention.

While chemical modification of oligonucleotide intemucleotide linkages with phosphorothioate, phosphorothioate, and/or 5 '-methylphosphonate linkages improves stability, too many of these modifications can cause some toxicity. Therefore when designing nucleic acid molecules the amount of these intemucleotide linkages should be minimized. The reduction in the concentration of these linkages should lower toxicity resulting in increased efficacy and higher specificity of these molecules.

Nucleic acid molecules having chemical modifications that maintain or enhance activity are provided. Such nucleic acid is also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity may not be significantly lowered. Therapeutic nucleic acid molecules delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. Clearly, nucleic acid molecules must be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA and DNA (Wincott et al, 1995 Nucleic Acids Res. 23, 2677; Caruthers et al, 1992, Methods in Enzymology 211,3-19 (incorporated by reference herein) have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above. In one embodiment, nucleic acid molecules of the invention include one or more G- clamp nucleotides. A G-clamp nucleotide is a modified cytosine analog wherein the modifications confer the ability to hydrogen bond both Watson-Crick and Hoogsteen faces of a complementary guanine within a duplex, see for example Lin and Matteucci, 1998, J. Am. Chem. Soc, 120, 8531-8532. A single G-clamp analog substitution within an oligonucleotide can result in substantially enhanced helical thermal stability and mismatch discrimination when hybridized to complementary oligonucleotides. The inclusion of such nucleotides in nucleic acid molecules of the invention results in both enhanced affinity and specificity to nucleic acid targets. In another embodiment, nucleic acid molecules of the mvention include one or more LNA "locked nucleic acid" nucleotides such as a 2', 4'-C mythylene bicyclo nucleotide (see for example Wengel et al, International PCT Publication No. WO 00/66604 and WO 99/14226).

In another embodiment, the invention features conjugates and/or complexes of nucleic acid molecules targeting VEGF receptors such as VEGFRl and/or VEGFR2. Such conjugates and/or complexes can be used to facilitate delivery of molecules into a biological system, such as cells. The conjugates and complexes provided by the instant invention can impart therapeutic activity by transferring therapeutic compounds across cellular membranes, altering the pharmacokinetics, and/or modulating the localization of nucleic acid molecules of the invention. The present invention encompasses the design and synthesis of novel conjugates and complexes for the delivery of molecules, including but not limited to small molecules, lipids, phospholipids, nucleosides, nucleotides, nucleic acids, antibodies, toxins, negatively charged polymers and other polymers, for example proteins, peptides, hormones, carbohydrates, polyethylene glycols, or polyamines, across cellular membranes. In general, the transporters described are designed to be used either individually or as part of a multi- component system, with or without degradable linkers. These compounds are expected to improve delivery and/or localization of nucleic acid molecules of the invention into a number of cell types originating from different tissues, in the presence or absence of serum (see Sullenger and Cech, US 5,854,038). Conjugates of the molecules described herein can be attached to biologically active molecules via linkers that are biodegradable, such as biodegradable nucleic acid linker molecules.

The term "biodegradable nucleic acid linker molecule" as used herein, refers to a nucleic acid molecule that is designed as a biodegradable linker to connect one molecule to another molecule, for example, a biologically active molecule. The stability of the biodegradable nucleic acid linker molecule can be modulated by using various combinations of ribonucleotides, deoxyribonucleotides, and chemically modified nucleotides, for example, 2'-O-methyl, 2'-fluoro, 2'-amino, 2'-O-amino, 2'-C-allyl, 2'-O-allyl, and other 2'-modified or base modified nucleotides. The biodegradable nucleic acid linker molecule can be a dimer, trimer, tetramer or longer nucleic acid molecule, for example, an oligonucleotide of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, or can comprise a single nucleotide with a phosphoms based linkage, for example, a phosphoramidate or phosphodiester linkage. The biodegradable nucleic acid linker molecule can also comprise nucleic acid backbone, nucleic acid sugar, or nucleic acid base modifications.

The term "biodegradable" as used herein, refers to degradation in a biological system, for example enzymatic degradation or chemical degradation.

The term "biologically active molecule" as used herein, refers to compounds or molecules that are capable of eliciting or modifying a biological response in a system. Non- limiting examples of biologically active molecules contemplated by the instant invention include therapeutically active molecules such as antibodies, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, 2,5-A chimeras, siRNA, dsRNA, allozymes, aptamers, decoys and analogs thereof. Biologically active molecules of the invention also include molecules capable of modulating the pharmacokinetics and/or pharmacodynamics of other biologically active molecules, for example, lipids and polymers such as polyamines, polya ides, polyethylene glycol and other polyethers.

The term "phospholipid" as used herein, refers to a hydrophobic molecule comprising at least one phosphoms group. For example, a phospholipid can comprise a phosphoms containing group and saturated or unsaturated alkyl group, optionally substituted with OH, COOH, oxo, amine, or substituted or unsubstituted aryl groups.

Therapeutic nucleic acid molecules (e.g., enzymatic nucleic acid molecules and antisense nucleic acid molecules) delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. These nucleic acid molecules should be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of nucleic acid molecules described in the instant invention and in the art have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.

In another embodiment, nucleic acid catalysts having chemical modifications that maintain or enhance enzymatic activity are provided. Such nucleic acids are also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity of the nucleic acid may not be significantly lowered. As exemplified herein such enzymatic nucleic acids are useful in a cell and/or in vivo even if activity over all is reduced 10 fold (Burgin et al, 1996, Biochemistry, 35, 14090). Such enzymatic nucleic acids herein are said to "maintain" the enzymatic activity of an all RNA ribozyme or all DNA DNAzyme.

In another aspect the nucleic acid molecules comprise a 5' and/or a 3'- cap structure.

By "cap structure" is meant chemical modifications, which have been incorporated at either terminus of the oligonucleotide (see for example Wincott et al, WO 97/26270, incorporated by reference herein). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5'-terminus (5'-cap) or at the 3'-terminus (3'-cap) or can be present on both terminus, hi non-limiting examples, the 5 '-cap includes inverted abasic residue (moiety), 4', 5 '-methylene nucleotide; l-(beta-D-erythrofuranosyl) nucleotide, 4'-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha- nucleotides; modified base nucleotide; phosphorodithioate linkage; tAreo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5- dihydroxypentyl nucleotide, 3 '-3 '-inverted nucleotide moiety; 3'-3'-inverted abasic moiety; 3'- 2'-inverted nucleotide moiety; 3'-2'-inverted abasic moiety; 1,4-butanediol phosphate; 3'- phosphoramidate; hexylphosphate; aminohexyl phosphate; 3'-phosphate; 3'-phosphorothioate; phosphorodithioate; or bridging or non-bridging methylphosphonate moiety (for more details see Wincott et al, Intemational PCT publication No. WO 97/26270, incorporated by reference herein).

In another embodiment the 3 '-cap includes, for example 4', 5 '-methylene nucleotide; 1- (beta-D-erythrofuranosyl) nucleotide; 4'-thio nucleotide, carbocyclic nucleotide; 5'-amino- alkyl phosphate; l,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; tΛreo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3, 5 -dihydroxypentyl nucleotide, 5'-5'-inverted nucleotide moiety; 5 -5 '-inverted abasic moiety; 5'-phosphoramidate; 5'-phosphorothioate; 1,4-butanediol phosphate; 5'-amino; bridging and/or non-bridging 5'-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5'-mercapto moieties (for more details see Beaucage and Iyer, 1993, Tetrahedron 49, 1925; incorporated by reference herein).

By the term "non-nucleotide" is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine.

An "alkyl" group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain, and cyclic alkyl groups. Preferably, the alkyl group has 1 to 12 carbons. More preferably it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkyl group can be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, =O, =S, NO₂ or N(CH3)₂, amino, or SH. The term also includes alkenyl groups which are unsaturated hydrocarbon groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkenyl group can be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, =O, =S, NO₂, halogen, N(CH₃)₂, amino, or SH. The term "alkyl" also includes alkynyl groups which have an unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkynyl group can be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, =O, =S, NO₂ or N(CH₃)₂, amino or SH.

Such alkyl groups can also include aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide and ester groups. An "aryl" group refers to an aromatic group which has at least one ring having a conjugated p electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which can be optionally substituted. The preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups. An "alkylaryl" group refers to an alkyl group (as described above) covalently joined to an aryl group (as described above). Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted. Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted. An "amide" refers to an -C(O)-NH-R, where R is either alkyl, aryl, alkylaryl or hydrogen. An "ester" refers to an -C(O)-OR', where R is either alkyl, aryl, alkylaryl or hydrogen.

By "nucleotide" is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a phosphorylated sugar. Nucleotides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1' position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. The nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and other; see for example, Usman and McSwiggen, supra; Eckstein et al, International PCT Publication No. WO 92/07065; Usman et al, International PCT Publication No. WO 93/15187; Uhhnan & Peyman, supra all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al, 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, for example, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, quesosine, 2- thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, 5- (carboxyhydroxymethyl)uridine, 5 '-carboxymethylaminomethyl-2-thiouridine, 5- carboxymethylaminomethyluridine, beta-D-galactosylqueosine, 1-methyladenosine, 1- methylinosine, 2,2-dimethylguanosine, 3-methylcytidine, 2-methyladenosine, 2- methylguanosine, N6-methyladenosine, 7-methylguanosine, 5-methoxyaminomethyl-2- thiouridine, 5-methylaminomethyluridine, 5-methylcarbonylmethyluridine, 5- methyloxyuridine, 5-methyl-2-thiouridine, 2-methylthio-N6-isopentenyladenosine, beta-D- mannosylqueosine, uridine-5-oxyacetic acid, 2-thiocytidine, threonine derivatives and others (Burgin et al, 1996, Biochemistry, 35, 14090; Uhhnan & Peyman, supra). By "modified bases" in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1' position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.

By "nucleoside" is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a sugar. Nucleosides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1' position of a nucleoside sugar moiety. Nucleosides generally comprise a base and sugar group. The nucleosides can be unmodified or modified at the sugar, and/or base moiety, (also referred to interchangeably as nucleoside analogs, modified nucleosides, non-natural nucleosides, non- standard nucleosides and other; see for example, Usman and McSwiggen, supra; Eckstein et al, Intemational PCT Publication No. WO 92/07065; Usman et al, International PCT Publication No. WO 93/15187; Uhhnan & Peyman, supra all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al, 1994, Nucleic Acids Res. 22, 2183. Some of the non- limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6- methyluridine), propyne, quesosine, 2-thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, 5-(carboxyhydroxymethyl)uridine, 5 '-carboxymethylaminomethyl-2- thiouridine, 5-carboxymethylaminomethyluridine, beta-D-galactosylqueosine, 1- methyladenosine, 1-methylinosine, 2,2-dimethylguanosine, 3-methylcytidine, 2- methyladenosine, 2-mefhylguanosine, N6-methyladenosine, 7-methylguanosine, 5- methoxyaminomethyl-2-thiouridine, 5-methylaminomethyluridine, 5- methylcarbonylmethyluridine, 5-methyloxyuridine, 5-methyl-2-thiouridine, 2-methylthio-N6- isopentenyladenosine, beta-D-mannosylqueosine, uridine-5-oxyacetic acid, 2-thiocytidine, threonine derivatives and others (Burgin et al, 1996, Biochemistry, 35, 14090; Uhhnan & Peyman, supra). By "modified bases" in this aspect is meant nucleoside bases other than adenine, guanine, cytosine and uracil at 1' position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.

hi one embodiment, the invention features modified enzymatic nucleic acid molecules with phosphate backbone modifications comprising one or more phosphorothioate, phosphorodithioate, methylphosphonate, morpholino, amidate carbamate, carboxymethyl, acetamidate, polyamide, sulfonate, sulfonamide, sulfamate, formacetal, thioformacetal, and/or alkylsilyl, substitutions. For a review of oligonucleotide backbone modifications see Hunziker and Leumann, 1995, Nucleic Acid Analogues: Synthesis and Properties, in Modern Synthetic Methods, VCH, 331-417, and Mesmaeker et al, 1994, Novel Backbone Replacements for Oligonucleotides, in Carbohydrate Modifications in Antisense Research, ACS, 24-39. These references are hereby incorporated by reference herein.

By "abasic" is meant sugar moieties lacking a base or having other chemical groups in place of a base at the 1' position, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative (for more details see Wincott et al, Intemational PCT publication No. WO 97/26270).

By "unmodified nucleoside" is meant one of the bases adenine, cytosine, guanine, thymine, uracil joined to the 1' carbon of β-D-ribo-furanose.

By "modified nucleoside" is meant any nucleotide base which contains a modification in the chemical structure of an unmodified nucleotide base, sugar and/or phosphate.

i connection with 2 '-modified nucleotides as described for the present invention, by

"amino" is meant 2'-NH₂ or 2'-0- NH₂, which can be modified or unmodified. Such modified groups are described, for example, in Eckstein et al, U.S. Patent 5,672,695 and

Matulic-Adamic et al, WO 98/28317, respectively, which are both incorporated by reference in their entireties.

Various modifications to nucleic acid (e.g., antisense and ribozyme) structure can be made to enhance the utility of these molecules. For example, such modifications can enhance shelf-life, half-life in vitro, stability, and ease of introduction of such oligonucleotides to the target site, including, e.g., enhancing penetration of cellular membranes and conferring the ability to recognize and bind to targeted cells.

Use of the nucleic acid-based molecules of the invention can lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs) and or other chemical or biological molecules). The treatment of patients with nucleic acid molecules can also include combinations of different types of nucleic acid molecules. Therapies can be devised which include a mixture of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs), allozymes, antisense, dsRNA, aptamers, and/or 2-5A chimera molecules to one or more targets to alleviate symptoms of a disease.

Administration of Nucleic Acid Molecules

Methods for the delivery of nucleic acid molecules are described in Akhtar et al., 1992, Trends Cell Bio., 2, 139; and Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995 which are both incorporated herein by reference. Sullivan et al, PCT WO 94/02595, further describes the general methods for delivery of enzymatic RNA molecules. These protocols can be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules can be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres. Alternatively, the nucleic acid/vehicle combination is locally delivered by direct injection or by use of an infusion pump. Other routes of delivery include, but are not limited to oral (tablet or pill form) and/or intrathecal delivery (Gold, 1997, Neuroscience, 76, 1153-1158). Other approaches include the use of various transport and carrier systems, for example though the use of conjugates and biodegradable polymers. For a comprehensive review on drag delivery strategies including CNS delivery, see Ho et al, 1999, Curr. Opin. Mol. Ther., 1, 336-343 and Jain, Drug Delivery Systems: Technologies and Commercial Opportunities, Decision Resources, 1998 and Groothuis et al, 1997, J. NeuroVirol, 3, 387-400. More detailed descriptions of nucleic acid delivery and administration are provided in Sullivan et al, supra, Draper et al, PCT WO93/23569, Beigehnan et al., PCT WO99/05094, and Klimuk et al, PCT WO99/04819 all of which have been incorporated by reference herein.

The molecules of the instant invention can be used as pharmaceutical agents. Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a patient.

The polynucleotides of the invention can be administered (e.g., RNA, DNA or protein) and introduced into a patient by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for formation of liposomes can be followed. The compositions of the present invention can also be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions; suspensions for injectable administration; and the other compositions known in the art.

The present invention also includes pharmaceutically acceptable formulations of the compounds described. These formulations include salts of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid.

A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., systemic administration, into a cell or patient, preferably a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms which prevent the composition or formulation from exerting its effect.

By "systemic administration" is meant in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Administration routes which lead to systemic absorption include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes expose the desired negatively charged polymers, e.g., nucleic acids, to an accessible diseased tissue. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach can provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as cells implicated in endometriosis, birth control, endometrial tumors, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), menopausal dysfunction, and endometrial carcinoma.

By pharmaceutically acceptable formulation is meant, a composition or formulation that allows for the effective distribution of the nucleic acid molecules of the instant invention in the physical location most suitable for their desired activity. Non-limiting examples of agents suitable for formulation with the nucleic acid molecules of the instant invention include: PEG conjugated nucleic acids, phospholipid conjugated nucleic acids, nucleic acids containing lipophilic moieties, phosphorothioates, P-glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of drugs into various tissues, for example the CNS (Jolliet- Riant and Tillement, 1999, Fundam. Clin. Pharmacol, 13, 16-26); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after implantation (Emerich, DF et al, 1999, Cell Transplant, 8, 47-58) Alkermes, hie. Cambridge, MA; and loaded nanoparticles, such as those made of polybutylcyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms (Prog Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999). Other non-limiting examples of delivery strategies, including CNS delivery of the nucleic acid molecules of the instant invention include material described in Boado et al, 1998, J. Pharm. Sci, 87, 1308-1315; Tyler et al, 1999, FEBS Lett, 421, 280-284; Pardridge et al, 1995, PNAS USA., 92, 5592- 5596; Boado, 1995, Adv. Drug Delivery Rev., 15, 73-107; Aldrian-Herrada et al, 1998, Nucleic Acids Res., 26, 4910-4916; and Tyler et al, 1999, PNAS USA., 96, 7053-7058. All these references are hereby incorporated herein by reference.

The invention also features the use of the composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). Nucleic acid molecules of the invention can also comprise covalently attached PEG molecules of various molecular weights. These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drag (Lasic et al. Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al, Chem. Pharm. Bull. 1995, 43, 1005-1011). Such liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized target tissues (Lasic et al, Science 1995, 267, 1275-1276; Oku et al, 1995, Biochim. Biophys. Ada, 1238, 86-90). The long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al, J. Biol. Chem. 1995, 42, 24864-24870; Choi et al, Intemational PCT Publication No. WO 96/10391; Ansell et al, Intemational PCT Publication No. WO 96/10390; Holland et al, International PCT Publication No. WO 96/10392; all of which are incorporated by reference herein). Long- circulating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen. All of these references are incorporated by reference herein.

The present invention also includes compositions prepared for storage or administration which include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985) hereby incorporated by reference herein. For example, preservatives, stabilizers, dyes and flavoring agents can be provided. These include sodium benzoate, sorbic acid and esters of p- hydroxybenzoic acid. In addition, antioxidants and suspending agents can be used.

A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer. The nucleic acid molecules of the invention and formulations thereof can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a nucleic acid molecule of the invention and a pharmaceutically acceptable carrier. One or more nucleic acid molecules of the invention can be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing nucleic acid molecules of the invention can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, com starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques, hi some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.

Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

Pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono-or diglycerides. hi addition, fatty acids such as oleic acid find use in the preparation of injectables. The nucleic acid molecules of the invention can also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drag with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

Nucleic acid molecules of the invention can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient.

It is understood that the specific dose level for any particular patient depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drag combination and the severity of the particular disease undergoing therapy.

For administration to non-human animals, the composition can also be added to the animal feed or drinking water. It can be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It can also be convenient to present the composition as a premix for addition to the feed or drinking water.

The nucleic acid molecules of the present invention can also be administered to a patient in combination with other therapeutic compounds to increase the overall therapeutic effect. The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects. Alternatively, certain of the nucleic acid molecules of the instant invention can be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc Natl. Acad. Sci, USA 83, 399; Scanlon et al, 1991, Proc. Nat Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al, 1992, Antisense Res. Dev., 2, 3-15; Dropulic et al, 1992, J. Virol, 66, 1432-41; Weerasinghe et al, 1991, J. Virol, 65, 5531-4; Ojwang et al, 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al, 1992, Nucleic Acids Res., 20, 4581-9; Sarver et al, 1990 Science, 247, 1222-1225; Thompson et al, 1995, Nucleic Acids Res., 23, 2259; Good et al, 1997, Gene Therapy, 4, 45; all of these references are hereby incorporated in their totalities by reference herein). Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a enzymatic nucleic acid (Draper et al, PCT WO 93/23569, and Sullivan et al, PCT WO 94/02595; Ohkawa et al, 1992, Nucleic Acids Symp. Ser., 27, 15-6; Taira et al, 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al, 1993, Nucleic Acids Res., 21, 3249-55; Chowrira et al, 1994, J. Biol. Chem., 269, 25856; all of these references are hereby incorporated in their totalities by reference herein). Gene therapy approaches specific to the CNS are described by Blesch et al, 2000, Drug News Perspect, 13, 269-280; Peterson et al, 2000, Cent. Nerv. Syst. Dis., 485-508; Peel and Klein, 2000, J. Neurosci Methods, 98, 95-104; Hagihara et al, 2000, Gene Ther., 7, 759-763; and Herrlinger et al, 2000, Methods Mol. Med., 35, 287-312. AAV-mediated delivery of nucleic acid to cells of the nervous system is further described by Kaplitt et al, US 6,180,613.

h another aspect of the invention, RNA molecules of the present invention are preferably expressed from transcription units (see for example Couture et al, 1996, TIG, 12, 510) inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors can be constructed based on, but not hmited to, adeno-associated vims, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the nucleic acid molecules are delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of nucleic acid molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the nucleic acid molecule binds to the target mRNA. Delivery of nucleic acid molecule expressing vectors can be systemic, such as by intravenous or intra-muscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review see Couture et al, 1996, TIG, 12, 510). hi one aspect the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the instant invention. The nucleic acid sequence encoding the nucleic acid molecule of the instant invention is operably linked in a manner which allows expression of that nucleic acid molecule.

In another aspect the invention features an expression vector comprising: a) a transcription initiation region (e.g., eukaryotic pol I, It or III initiation region); b) a transcription termination region (e.g., eukaryotic pol I, π or m termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. The vector can optionally include an open reading frame (ORF) for a protein operably linked on the 5' side or the 3'-side of the sequence encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).

Transcription of the nucleic acid molecule sequences are driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol H), or RNA polymerase UI (pol IH). Transcripts from pol II or pol IU promoters are expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl Acad. Sci. US -4, 87, 6743-7; Gao and Huang 1993, Nucleic Acids Res.., 21, 2867-72; Lieber et al, 1993, Methods Enzymol, 217, 47-66; Zhou et al, 1990, Mol. Cell. Biol, 10, 4529-37). All of these references are incorporated by reference herein. Several investigators have demonstrated that nucleic acid molecules, such as ribozymes expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al, 1992, Antisense Res. Dev., 2, 3- 15; Ojwang et al, 1992, Proc. Natl. Acad. Sci. U S A, 89, 10802-6; Chen et al, 1992, Nucleic Acids Res., 20, 4581-9; Yu et al, 1993, Proc. Natl. Acad. Sci. USA, 90, 6340-4; L'Huillier et al, 1992, EMBO , 11, 4411-8; Lisziewicz et al, 1993, Proc. Natl. Acad. Sci. U. S. A, 90, 8000-4; Thompson et al, 1995, Nucleic Acids Res., 23, 2259; Sullenger & Cech, 1993, Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al, supra; Couture and Stinchcomb, 1996, supra; Noonberg et al, 1994, Nucleic Acid Res., 22, 2830; Noonberg et al, US Patent No. 5,624,803; Good et al, 1997, Gene Tlier., 4, 45; Beigehnan et al, Intemational PCT Publication No. WO 96/18736; all of these publications are incorporated by reference herein. The above ribozyme transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchconib, 1996, supra).

hi another aspect the invention features an expression vector comprising nucleic acid sequence encoding at least one of the nucleic acid molecules of the invention, in a manner which allows expression of that nucleic acid molecule. The expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

hi another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3'-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In yet another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

In another embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3 '-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

Flt-1 (VEGFRl), KDR (VEGFR2) and/or flk-1 are attractive nucleic acid-based therapeutic targets by several criteria. The interaction between VEGF and VEGF-R is well- established. Efficacy can be tested in well-defined and predictive animal models. Finally, the disease conditions are serious and current therapies are inadequate. Whereas protein-based therapies are designed to affect VEGF activity, nucleic acid-based therapy based on the molecules and methods described herein provides a direct and elegant approach to directly modulate flt-1, KDR and/or flk-1 expression.

Because VEGFRl and VEGFR2 mRNAs are highly homologous in certain regions, some nucleic acid target sites are also homologous. In this case, a single nucleic acid molecule of the invention can target both VEGFRl and VEGFR2 mRNAs. At partially homologous sites, a single nucleic acid molecule can sometimes be designed to accommodate a site on both mRNAs by including G/U base pairing. For example, if there is a G present in a enzymatic nucleic acid target site in VEGFRl mRNA at the same position there is an A in the VEGFR2 enzymatic nucleic acid target site, the enzymatic nucleic acid can be synthesized with a U at the complementary position and it will bind both to sites. The advantage of one enzymatic nucleic acid that targets both VEGFRl and VEGFR2 mRNAs is clear, especially in cases where both VEGF receptors may contribute to the progression of angiogenesis in the disease state. Examples

The following are non-limiting examples showing the selection, isolation, synthesis and activity of exemplary nucleic acids of the instant invention.

The following examples demonstrate the selection and design of antisense, aptamer, dsRNA, allozyme, hammerhead, DNAzyme, NCH, Amberzyme, Zinzyme, or G-Cleaver ribozyme molecules and binding/cleavage sites within VEGF, VEGFRl and/or VEGFR2

RNA.

Example 1 : Enzymatic nucleic acid-mediated inhibition of angiogenesis in vivo

The study described below was performed to assess the anti-angiogenic activity of hammerhead ribozymes targeted against flt-1 4229 site (SED ID NO: 5977) in the rat cornea model of VEGF induced angiogenesis (see above). These ribozymes have either active or inactive catalytic core and either bind and cleave or just bind to VEGF-R mRNA of the flt-1 subtype. The active ribozymes, that are able to bind and cleave the target RNA, have been shown to inhibit (¹²⁵I-labeled) VEGF binding in cultured endothelial cells and produce a dose-dependent decrease in VEGF induced endothelial cell proliferation in these cells. The catalytically inactive forms of these ribozymes, which can only bind to the RNA but cannot catalyze RNA cleavage, failed to inhibit VEGF binding and failed to decrease VEGF induced endothelial cell proliferation. The ribozymes and VEGF were co-delivered using the filter disk method: Nitrocellulose filter disks (Millipore®) of 0.057 diameter were immersed in appropriate solutions and were surgically implanted in rat cornea as described by Pandey et al, supra. This delivery method has been shown to deliver rhodamine-labeled free ribozyme to scleral cells and, in all likelihood cells of the pericorneal vascular plexus. Since the active ribozymes show cell culture efficacy and can be delivered to the target site using the disk method, it is essential that these ribozymes be assessed for in vivo anti-angiogenic activity.

The stimulus for angiogenesis in this study was the treatment of the filter disk with 30 μM VEGF which is implanted within the cornea's stroma. This dose yields reproducible neovascularization stemming from the pericorneal vascular plexus growing toward the disk in a dose-response study 5 days following implant. Filter disks treated only with the vehicle for VEGF show no angiogenic response. The ribozymes were co-adminstered with VEGF on a disk in two different ribozyme concentrations. One concern with the simultaneous administration is that the ribozymes will not be able to inhibit angiogenesis since VEGF receptors can be stimulated. However, we have observed that in low VEGF doses, the neovascular response reverts to normal suggesting that the VEGF stimulus is essential for maintaining the angiogenic response. Blocking the production of VEGF receptors using simultaneous administration of anti- VEGF-R mRNA ribozymes could attenuate the normal neovascularization induced by the filter disk treated with VEGF.

Materials and Methods: 1. Stock hammerhead ribozyme solutions: a. flt-1 4229 (786 μM)- Active

b. flt-1 4229 (736 μM)- Inactive

2. Experimantal solutions/groups:

Group 1 Solution 1 Control VEGF solution: 30 μM in 82mM Tris base

Group 2 Solution 2 flt-1 4229 (1 μg/μL) in 30 μM VEGF/82 mM Tris base

Group 3 Solution 3 flt-1 4229 (10 μg/μL) in 30 μM VEGF/82 mM Tris base

Group 4 Solution 4 No VEGF, flt-1 4229 (10 μg/μL) in 82 mM Tris base Group 5 Solution 5 No VEGF, No ribozyme in 82 mM Tris base 10 eyes per group, 5 animals (Since they have similar molecular weights, the molar concentrations should be essentially similar).

Each solution (VEGF and RIBOZYMES) were prepared as a 2X solution for 1 : 1 mixing for final concentrations above, with the exception of solution 1 in which VEGF was 2X and diluted with ribozyme diluent (sterile water).

3. VEGF Solutions

The 2X VEGF solution (60 μM) was prepared from a stock of 0.82 μg/μL in 50 mM Tris base. 200 μL of VEGF stock was concentrated by speed vac to a final volume of 60.8 μL, for a final concentration of 2.7 μg/μL or 60 μM. Six 10 μL aliquots was prepared for daily mixing. 2X solutions for VEGF and Ribozyme was stored at 4°C until the day of the surgery. Solutions were mixed for each day of surgery. Original 2X solutions was prepared on the day before the first day of the surgery.

4. Surgical Solutions:

Anesthesia:

stock ketamine hydrochloride 100 mg/mL

stock xylazine hydrochloride 20 mg/mL

stock acepromazine 10 mg/mL

Final anesthesia solution: 50 mg/mL ketamine, 10 mg/mL xylazine, and 0.5 mg/mL acepromazine

5% povidone iodine for opthahnic surgical wash

2% lidocaine (sterile) for opthahnic administration (2 drops per eye)

sterile 0.9% NaCl for opthalmic irrigation

5. Surgical Methods:

Standard surgical procedure as described in Pandey et al, supra. Filter disks were incubated in 1 μL of each solution for approximately 30 minutes prior to implantation.

6. Experimental Protocol: The animal cornea were treated with the treatment groups as described above. Animals were allowed to recover for 5 days after treatment with daily observation (scoring 0 - 3). On the fifth day animals were euthanized and digital images of each eye was obtained for quantitaion using Image Pro Plus. Quantitated neovascular surface area were analyzed by ANOVA followed by two post-hoc tests including Dunnets and Tukey-Kramer tests for significance at the 95% confidence level. Dunnets provide information on the significance between the differences within the means of treatments vs. controls while Tukey-Kramer provide information on the significance of differences within the means of each group.

The flt-1 4229 (SEQ ID NO: 5977) active hammerhead ribozyme at both concentrations was effective at inhibiting angiogenesis while the inactive ribozyme did not show any significant reduction in angiogenesis. A statistically signifiant reduction in neovascular surface area was observed only with active ribozymes. This result clearly shows that the ribozymes are capable of significantly inhibiting angiogenesis in vivo. Specifically, given ribozyme mechanism of action, the observed inhibition is by the binding and cleavage of target RNA by ribozymes.

Example 2: Bioactivity of anti-angio enesis ribozymes targeting flt-1 and kdr RNA

MATERIALS AND METHODS

Ribozymes : Hammerhead ribozymes and controls designed to have attenuated activity (attenuated controls) were synthesized and purified as previously described above. The attenuated ribozyme controls maintain the binding arm sequence of the parent ribozyme and thus are still capable of binding to the mRNA target. However, they have two nucleotide changes in the core sequence that substantially reduce their ability to carry out the cleavage reaction. Ribozymes were designed to target Flt-1 or KDR mRNA sites conserved in human, mouse, and rat. In general, ribozymes with binding arms of seven nucleotides were designed and tested. If, however, only six nucleotides surrounding the cleavage site were conserved in all three species, six nucleotide binding arms were used. Data are presented herein for 2'-NH₂ uridine modified ribozymes in cell proliferation studies and for 2'-C-allyl uridine modified ribozymes in RNAse protection, in vitro cleavage and comeal studies.

In vitro ribozyme cleavage assays: In vitro RNA cleavage rates on a 15 nucleotide synthetic RNA substrate were measured as previously described above.

Cell culture: Human dermal microvascular endothelial cells (HMVEC-d, Clonetics Corp.) were maintained at 37 C in flasks or plates coated with 1.5% porcine skin gelatin (300 bloom, Sigma) in Growth medium (Clonetics Corp.) supplemented with 10-20% fetal bovine serum (FBS, Hyclone). Cells were grown to confluency and used up to the seventh passage. Stimulation medium consisted of 50% Sigma 99 media and 50% RPMI 1640 with L- glutamine and additional supplementation with 10 μg/mL lhsulin-Transferrin-Selenium (Gibco BRL) and 10% FBS. Cell growth was stimulated by incubation in Stimulation medium supplemented with 20 ng/mL of either VEGF₁₆₅ or bFGF. VEGF₁₆₅ (165 amino acids) was selected for cell culture and animal studies because it is the predominant form of the four native forms of VEGF generated by alternative mRNA splicing. Cell culture assays were carried out in triplicate.

Ribozyme and ribozyme/ iPOFECT AMINE™ formulations :

Cell culture: Ribozymes or attenuated controls (50-200 nM) were formulated for cell culture studies and used immediately. Formulations were carried out with LlPOFECTAMINE™ (Gibco BRL) at a 3:1 lipid to phosphate charge ratio in serum-free medium (OPTI-MEM™, Gibco BRL) by mixing for 20 minutes at room temperature. For example, a 3:1 lipid to phosphate charge ratio was established by complexing 200 nM ribozyme with 10.8 μg/μL LlPOFECTAMINE™ (13.5 μM DOSPA).

In vivo: For comeal studies, lyophilized ribozyme or attenuated controls were resuspended in sterile water at a final stock concentration of 170 μg/μL (highest dose). Lower doses (1.7-50 μg/μL) were prepared by serial dilution in sterile water.

Proliferation assay: HMVEC-d were seeded (5 x 10³ cells/well) in 48-well plates

(Costar) and incubated 24-30 hours in Growth medium at 37°C. After removal of the Growth medium, cells were treated with 50-200 nM LlPOFECTAMINE™ complexes of ribozyme or attenuated controls for 2 hours in OPTI-MEM™. The ribozyme/control-containing medium was removed and the cells were washed extensively in IX PBS. The medium was then replaced with Stimulation medium or Stimulation medium supplemented with 20 ng/mL VEGF₁₆5 or bFGF. After 48 hours, the cell number was determined using a Coulter™ cell counter. Data are presented as cell number per well following 48 hours of VEGF stimulation.

RNAse protection assay: HMVEC-d were seeded (2 x 10⁵ cells/well) in 6-well plates (Costar) and allowed to grow 32-36 hours in Growth medium at 37°C. Cells were treated with LlPOFECTAMINE™ complexes containing 200 nM ribozyme or attenuated control for 2 h as described under "Proliferation Assay" and then incubated in Growth medium containing 20 ng/mL VEGFι₆₅ for 24 hours. Cells were harvested and an RNAse protection assay was carried out using the Ambion Direct Protect kit and protocol with the exception that 50 mM EDTA was added to the lysis buffer to eliminate the possibility of ribozyme cleavage during sample preparation. Antisense RNA probes targeting portions of Flt-1 and KDR were prepared by transcription in the presence of [³²P]-UTP. Samples were analyzed on polyacrylamide gels and the level of protected RNA fragments was quantified using a Molecular Dynamics Phosphorhnager. The levels of Flt-1 and KDR were normalized to the level of cyclophilin (human cyclophilin probe template, Ambion) in each sample. The coefficient of variation for cyclophilin levels was 11% [265940 cpm ± 29386 (SD)] for all conditions tested here (ie. in the presence of either active ribozymes or attenuated controls). Thus, cyclophilin is useful as an internal standard in these studies.

Rat corneal pocket assay of VEGF-induced angiogenesis:

Animal guidelines and anesthesia. Animal housing and experimentation adhered to standards outlined in the 1996 Guide for the Care and Use of Laboratory Animals (National Research Council). Male Sprague Dawley rats (250-300 g) were anesthetized with ketamine (50 mg kg), xylazine (10 mg/kg), and acepromazine (0.5 mg/kg) administered intramuscularly (im). The level of anesthesia was monitored every 2-3 min by applying hind limb paw pressure and examining for limb withdrawal. Atropine (0.4 mg/kg, im) was also administered to prevent potential comeal reflex-induced bradycardia.

Preparation of VEGF soaked disk For comeal implantation, 0.57 mm diameter nitrocellulose disks, prepared from 0.45 μm pore diameter nitrocellulose filter membranes (Millipore Corporation), were soaked for 30 min in 1 μL of 30 μM VEGF₁₆₅ in 82 mM TrisΗCl (pH 6.9) in covered petri dishes on ice.

Corneal surgery. The rat comeal model used in this study was a modified from Koch et al Supra and Pandey et al, supra. Briefly, corneas were irrigated with 0.5% povidone iodine solution followed by normal saline and two drops of 2% lidocaine. Under a dissecting microscope (Leica MZ-6), a stromal pocket was created and a presoaked filter disk (see above) was inserted into the pocket such that its edge was 1 mm from the comeal linibus.

Intraconjunctival injection of test solutions. Immediately after disk insertion, the tip of a 40-50 μm OD injector (constructed in our laboratory) was inserted within the conjunctival tissue 1 mm away from the edge of the comeal limbus that was directly adjacent to the VEGF-soaked filter disk. Six hundred nanoliters of test solution (ribozyme, attenuated control or sterile water vehicle) were dispensed at a rate of 1.2 μlJmin using a syringe pump (Kd Scientific). The injector was then removed, serially rinsed in 70% ethanol and sterile water and immersed in sterile water between each injection. Once the test solution was injected, closure of the eyelid was maintained using microaneurism clips until the animal began to recover gross motor activity. Following treatment, animals were warmed on a heating pad at 37°C.

Animal treatment groups/experimental protocol Ribozymes targeting Flt-1 site 4229 (SEQ JO NO: 5977) and KDR mRNA site 726 (SEQ ID NO: 5978) were tested in the comeal model along with their attenuated controls. Five treatment groups were assigned to examine the effects of five doses of each test substance over a dose range of 1-100 μg on VEGF- stimulated angiogenesis. Negative (30 μM VEGF soaked filter disk and intraconjunctival injection of 600 nL sterile water) and no stimulus (Tris-soaked filter disk and intraconjunctival injection of sterile water) control groups were also included. Each group consisted of five animals (10 eyes) receiving the same treatment.

Quantitation of angiogenic response. Five days after disk implantation, animals were euthanized following im administration of 0.4 mg/kg atropine and corneas were digitally imaged. The neovascular surface area (NSA, expressed in pixels) was measured postmortem from blood-filled comeal vessels using computerized morphometry (Image Pro Plus, Media Cybernetics, v2.0). The individual mean NSA was determined in triplicate from three regions of identical size in the area of maximal neovascularization between the filter disk and the limbus. The number of pixels corresponding to the blood-filled comeal vessels in these regions was su mated to produce an index of NSA. A group mean NSA was then calculated. Data from each treatment group were normalized to VEGF/ribozyme vehicle-treated control NSA and finally expressed as percent inhibition of VEGF-induced angiogenesis.

Statistics. After determining the normality of treatment group means, group mean percent inhibition of VEGF-induced angiogenesis was subjected to a one-way analysis of variance. This was followed by two post-hoc tests for significance including Dunnett' s (comparison to VEGF control) and Tukey-Kramer (all other group mean comparisons) at alpha = 0.05. Statistical analyses were performed using JMP v.3.1.6 (SAS Institute).

RESULTS

Ribozyme-mediated reduction of VEGF-induced cell proliferation: Ribozyme cleavage of Flt-1 or KDR mRNA should result in a decrease in the density of cell surface VEGF receptors. This decrease should limit VEGF binding and consequently interfere with the mitogenic signaling induced by VEGF. To determine if cell proliferation was impacted by s&Xi-Flt-l and/or anti-ZDR ribozyme treatment, proliferation assays using cultured human microvascular cells were carried out. Ribozymes included in the proliferation assays were initially chosen by their ability to decrease the level of VEGF binding to treated cells, hi these initial studies, ribozymes targeting 20 sites in the coding region of each mRNA were screened. The most effective ribozymes against two sites in each target, Flt-1 sites 1358 and 4229 and KDR sites 726 and 3950, were included in the proliferation assays reported here. In addition, attenuated analogs of each ribozyme were used as controls. These attenuated controls are still capable of binding to the mRNA target since the binding arm sequence is maintained. However, these controls have two nucleotide changes in the core sequence that substantially reduce their ability to carry out the cleavage reaction.

The active ribozymes tested decreased the relative proliferation of HMVEC-d after VEGF stimulation, an effect that increased with ribozyme concentration. This concentration dependency was not observed following treatment with the attenuated controls designed for these sites, hi fact, little or no change in cell growth was noted following treatment with the attenuated controls, even though these controls can still bind to the specific target sequences. At 200 nM, there was a distinct "window" between the anti-proliferative effects of each ribozyme and its attenuated control; a trend also observed at lower doses. This window of inhibition of proliferation (56-77% based on total cells/well) reflects the contribution of ribozyme-mediated activity, hi comparison, no effect of anti- /t- or \i-KDR ribozymes was noted on bFGF-stimulated cell proliferation. Moreover, an irrelevant, but active, ribozyme whose binding sequence is not found in either Flt-1 or KDR mRNA had no effect in this assay. These data are consistent with the basic ribozyme mechanism in which binding and cleavage are necessary components. Although the relative surface distribution of Flt-1 and KDR receptors in this cell type is not known, the antiproliferative effects of these ribozymes indicate that, at least in cell culture, both receptors are functionally coupled to proliferation.

Specific reduction oϊ Flt-1 or KDR mRNA by ribozyme treatment: To confirm that anti- /t-i and anti-KDR ribozymes reduce their respective mRNA targets, cellular levels of Flt-1 or KDR were quantified using an RNAse protection assay with specific Flt-1 or KDR probes. For each target, one ribozyme/attenuated control pair was chosen for continued study. Exposure of HMVEC-d to active ribozyme targeting Flt-1 site 4229 decreased Flt-1 mRNA, but not KDR mRNA. Likewise, treatment with the active ribozyme targeting KDR site 726 decreased KDR, but not Flt-1 mRNA. Both ribozymes decreased the level of their respective target RNA by greater than 50%. The degree of reduction associated with the corresponding attenuated controls was not greater than 13%.

In vitro activity of anti-Fit and αnti-KDR ribozymes. To confirm further the necessity of an active ribozyme core, in vitro cleavage activities were determined for the Flt-1 site 4229 ribozyme and the KDR site 726 ribozyme as well as their paired attenuated controls. The first order rate constants calculated from the time-course of short substrate cleavage for the anti-Flt-1 ribozyme and its attenuated control were 0.081 ± 0.0007 min^"1 and 0.001 ± 6 x 10^-5 min^"1, respectively. For the arύi-KDR ribozyme and its paired control, the first order rate constants were 0.434 ± 0.024 min ^l and 0.002 ± 1 x 10^"4 min^"1, respectively. Although the attenuated controls retain a very slight level of cleavage activity under these optimized conditions, the decrease in in vitro cleavage activity between each active ribozyme and its paired attenuated control is about two orders of magnitude. Thus, an active core is essential for cleavage activity in vitro and is also necessary for ribozyme activity in cell culture.

Ribozyme-mediated reduction of VEGF-induced angiogenesis in vivo. To assess whether ribozymes targeting VEGF receptor mRNA could impact the complex process of angiogenesis, prototypic mti-Flt-1 and KDR ribozymes that were identified in cell culture studies were screened in a rat comeal pocket assay of VEGF-induced angiogenesis. In this assay, corneas implanted with VEGF-containing filter disks exhibited a robust neovascular response in the comeal region between the disk and the comeal limbus (from which the new vessels emerge). Disks containing a vehicle solution elicited no angiogenic response. In separate studies, intraconjunctival injections of sterile water vehicle did not affect the magnitude of the VEGF-induced angiogenic response, hi addition, ribozyme injections alone did not induce angiogenesis.

The dose-related effects of anti-Flt-1 or KDR ribozymes on the VEGF-induced angiogenic response were then examined. The antiangiogenic effect of the arάi-Flt-1 (site 4229) and KDR (site 726) ribozymes and their attenuated controls over a dose range from 1 to 100 μg, respectively was determined. For both ribozymes, the maximal antiangiogenic response (48 and 36% for axAi-Flt-1 and KDR ribozymes, respectively) was observed at a dose of 10 μg.

The dxxXi-Flt-1 ribozyme produced a significantly greater antiangiogenic response than its attenuated control at 3 and 10 μg (p<0.05). Its attenuated control exhibited a small but significant antiangiogenic response at doses above 10 μg compared to vehicle treated VEGF controls (p<0.05). At its maximum, this response was not significantly greater than that observed with the lowest dose of active anti- t-i ribozyme. The mti-KDR ribozyme significantly inhibited angiogenesis from 3 to 30 μg (p<0.05). The a ti-KDR attenuated control had no significant effect at any dose tested. Example 3. In vivo inhibition of tumor growth and metastases by VEGF-R ribozymes.

A. Lewis Lung Carcinoma Mouse Model: Ribozymes were chemically synthesized as described above. The sequence of ANGIOZYME™ bound to its target RNA is shown in Figure 1.

The tumors in this study were derived from a cell line (LLC-HM) which gives rise to reproducible numbers of spontaneous lung metastases when propagated in vivo. The LLC- HM line was obtained from Dr. Michael O'Reilly, Harvard University. Tumor neovascularization in Lewis lung carcinoma has been shown to be VEGF-dependent. Tumors from mice bearing LLC-HM (selected for the highly metastatic phenotype by serial propagation) were harvested 20 days post-inoculation. A tumor brei suspension was prepared from these tumors according to standard protocols. On day 0 of the study, 0.5 x 10⁶ viable LLC-HM tumor cells were injected subcutaneously (sc) into the dorsum or flank of previously untreated mice (100 μL injectate). Tumors were allowed to grow for a period of 3 days prior to initiating continuous intravenous administration of saline or 30 mg/kg/d ANGIOZYME™ via Alzet mini-pumps. One set of animals was dosed from days 3 to 17, inclusive. Tumor length and width measurements and volumes were calculated according to the formula: Volume = 0.5(length)(width)². At post-inoculation day 25, animals were euthanized and lungs harvested. The number of lung macrometastatic nodules was counted. It should be noted that metastatic foci were quantified 8 days after the cessation of dosing. Ribozyme solutions were prepared to deliver to another set of animals 100, 10, 3, or 1 mg/kg/day of ANGIOZYME™ via Alzet mini-pumps. A total of 10 animals per dose or saline control group were surgically implanted on the left flank with osmotic mini-pumps pre- filled with the respective test solution three days following tumor inoculation. Pumps were attached to indwelling jugular vein catheters.

Figure 2 shows the antitumor effects of ANGIOZYME™. There is a statistically significant inhibition (p < 0.05) of primary LLC-HM tumor growth in tumors grown in the flank regions compared to saline control. ANGIOZYME™ significantly reduced (p < 0.05) the number of lung metastatic foci in animals inoculated either in the flank regions. Figure 3 illustrates the dose-dependent anti-metastatic effect of ANGIOZYME™ compared to saline control.

B. Mouse Colorectal Cancer Model. KM12L4a-16 is a human colorectal cancer cell line. On day 0 of the study, 0.5 x 10 KM12L4a-16 cells were implanted into the spleen of nude mice. Three days after tumor inoculation, Alzet minipumps were implanted and continuous subcutaneous delivery of either saline or 12, 36 or 100 mg/kg/ day of ANGIOZYME™ was initiated. On day 5, the spleens containing the primary tumors were removed. On day 18, the Alzet minipumps were replaced with fresh pumps so that delivery of saline or ANGIOZYME™ was continuous over a 28 day period from day 3 to day 32. Animals were euthanized on day 41 and the liver tumor burden was evaluated.

Following treatment with 100 mg/kg/day of ANGIOZYME™, there was a significant reduction in the incidence and median number of liver metastasis (Figure 4). In saline- treated animals, the median number of metastases was 101. However, at the high dose of ANGIOZYME™ (100 mg/kg/day), the median number of metastases was zero.

Example 4: Effect of ANGIOZYME™ alone or in combination with chemotherapeutic agents in the mouse Lewis Lung Carcinoma Model.

Methods Tumor inoculations. Male C57/BL6 mice, age 6 to 8 weeks, were inoculated subcutaneously in the flank with 5 x 10⁵ LLC-HM cells from brei preparations made from tumors grown in mice. Ribozymes and controls. RPI.4610, also known as ANGIOZYME™ (SEQ ID NO:

5977), is an mti-Flt-1 ribozyme that targets site 4229 in the human Flt-1 receptor mRNA (EMBL accession no. X51602). The controls tested include RPI.13141, an attenuated version of RPI.4610 in which four nucleotides in the catalytic core are changed so that the cleavage activity is dramatically decreased. RPI.13141, however, maintains the base composition and binding arms of RPI.4610 and so is still capable of binding to the target site. The second control (RPI.13030) also has changes to the catalytic core (three) to inhibit cleavage activity, but in addition the sequence of the binding arms has been scrambled so that it can no longer bind to the target sequence. One nucleotide in the arm of RPI.13030 is also changed to maintain the same base composition as RPI.4610.

Ribozyme administrations. Ribozymes and controls were resuspended in normal saline. Administration was initiated seven days following tumor inoculation. Animals either received a daily subcutaneous injection (30 mg/kg test substance) from day 7 to day 20 or were instrumented with an Alzet osmotic minipump (12 μL/day flow rate) containing a solution of ribozyme or control. Subcutaneous infusion pumps delivered the test substances (30 mg kg/day) from day 7 to 20 (14-day pumps, 420 mg/kg total test substance) or days 7-34 (28-day pumps, 840 mg/kg total test substance). Where indicated, chemotherapeutic agents were given in combination with ribozyme treatment. Cyclophosphamide was given by intraperitoneal administration on days 7, 9 and 11 (125 mg/kg). Gemcitabine was given by intraperitoneal administration on days 8, 11 and 14 (125 mg/kg). Untreated, uninstrumented animals were used as comparison. Five animals were included in each group.

Results

The antiangiogenic ribozyme, ANGIOZYME™, was tested in a model of Lewis lung carcinoma alone and in combination with two chemotherapeutic agents. Previously (see above), 30 mg/kg/day ANGIOZYME™ alone was determined to inhibit both primary tumor growth and lung metastases in a highly metastatic variant of Lewis lung (continuous 14-day iv deliveryvtα Alzet minipump, manuscript in preparation). In this study, 30 mg/kg/day ANGIOZYME™ delivered either as a daily subcutaneous bolus injection or as a continuous infusion from an Alzet minipump resulted in a delay in tumor growth. On average, tumor growth to 500 mm was delayed by ~7 days in animals being treated with ANGIOZYME™ compared to an unfreated group. Growth of tumors in animals being treated with either of two attenuated controls was delayed by only ~ 2 days.

ANGIOZYME™ delivered by subcutaneous bolus was also tested in combination with either Gemcytabine or cyclophosphamide. Tumor growth delay increased by about 3 days in the presence of combination therapy with ANGIOZYME™ and Gemcytabine over the effects of either treatment alone. The combination of ANGIOZYME™ and cyclophosphamide did not increase tumor growth delay over that of cyclophosphamide alone, however, suboptimal doses of cyclophosphamide were not included in this study. Neither of the attenuated controls increased the effect of the chemotherapeutic agents.

The effect of ANGIOZYME™ on metastases to the lung was also determined in the presence and absence of additional chemotherapeutic freatment. Macrometastases to the lungs were counted in two animals in each treatment group on day 20. In the presence of ANGIOZYME™, with or without a chemotherapeutic agent, the lung metastases were reduced to zero. Treatment with either Gemcytabine or cyclophosphamide alone (mean number of metastases 4.5 and 4, respectively) were not as effective as ANGIOZYME™ alone or when used in combination with ANGIOZYME™. Neither of the attenuated controls increased the effect of the chemotherapeutic agents.

The effect on metastases to the lung was also determined following continuous treatment with ANGIOZYME™. At day 20, an average of ~8 macrometastases were noted in the treatment groups which had been instrumented with Alzet minipumps (either 14- or 28- day pumps). This is a decrease in metastases of ~50% from the untreated group. Since ANGIOZYME™ delivered by a daily subcutaneous bolus resulted in zero metastases (Fig.4) in the two animals counted, it is possible that the additional burden of being instrumented with the minipump contributes to a slightly decreased response to ANGIOZYME™.

Example 5: Identification of Potential Target Sites in Human VEGFRl and/or VEGFR2 RNA

The sequence of human VEGFRl and/or VEGFR2 genes are screened for accessible sites using a computer-folding algorithm. Regions of the RNA that do not form secondary folding structures and contain potential enzymatic nucleic acid molecule and/or antisense binding/cleavage sites are identified. An exemplary sequence of an enzymatic nucleic acid molecule of the invention is shown in Formula I and/or Formula JJ (SEQ ID Nos: 5977 and 5978, respectively). Other nucleic acid molecules and targets contemplated by the invention are described in Pavco et al, US Patent Application No. 09/870,161, incorporated by reference herein in its entirety. Similarly, other nucleic acid molecules of the invention, including antisense, aptamers, dsRNA, siRNA, and/or 2,5-A chimeras, can be designed to modulate the expression of the nucleic acid targets described in Pavco et al, US Patent Application No. 09/870,161.

Example 6: Selection of Enzymatic Nucleic Acid Cleavage Sites in Human VEGFRl and/or VEGFR2 RNA

Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of human VEGFRl receptor (for example Genbank Accession No. NM_002019), and VEGFR2 receptor (for example Genbank Accession No. NM_002253) genes and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al, 1994 J. Mol. Struc Theochem, 311, 273; Jaeger et al, 1989, Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the enzymatic nucleic acid molecule sequences fold into the appropriate secondary structure. Those enzymatic nucleic acid molecules with unfavorable intramolecular interactions between the binding arms and the catalytic core can be eliminated from consideration. As discussed herein, varying binding arm lengths can be chosen to optimize activity. Generally, at least 4 bases on each arm are able to bind to, or otherwise interact with, the target RNA.

Example 7: Chemical Synthesis and Purification of Ribozymes and Antisense for Efficient Cleavage and/or blocking of VEGFRl and/or VEGFR2 RNA Enzymatic nucleic acid molecules and antisense constructs are designed to anneal to various sites in the RNA message. The binding arms of the enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constructs are fully complementary to the target site sequences described above. RNAi molecules (dsRNA) likewise have one strand of RNA or a portion of RNA complementarity to the target site sequence or a portion of the target site sequence. For example, complementarity within the double-strand RNAi structure is formed from two separate individual RNA strands or from self-complementary areas of a topologically closed, individual RNA sfrand which can be optionally circular. The nucleic acid molecules were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al, (1987 J. Am. Chem. Soc, 109, 7845), Scaringe et al, (1990 Nucleic Acids Res., 18, 5433) and Wincott et al, supra, and made use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. The average stepwise coupling yields were typically >98%.

Nucleic acid molecules are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Nucleic acid molecules of the invention are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al, supra; the totality of which is hereby incorporated herein by reference) and are resuspended in water. Examples of sequences of chemically synthesized enzymatic nucleic acid molecules are shown in Formula I (SEQ ID NO: 5977), Formula II (SEQ ID NO: 5978) and in Pavco et al, US Patent Application No. 09/870, 161.

Example 8: Enzymatic Nucleic Acid Molecule Cleavage of VEGFRl and/or VEGFR2 RNA Target in vitro

Enzymatic nucleic acid molecules targeted to the human VEGFRl and/or VEGFR2

RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure. The target sequences and the nucleotide location within the VEGFRl and/or VEGFR2 RNA are described in Pavco et al, US Patent Application No. 09/870,161.

Cleavage Reactions: Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a-³ p] CTP, passed over a G 50 Sephadex column by spin chromatography and used as substrate RNA without further purification. Alternately, substrates are 5'-32p-end labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2X concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HCl, pH 7.5 at 37°C, 10 mM M Ci2) and the cleavage reaction was initiated by adding the 2X enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an initial screen, assays are carried out for 1 hour at 37 C using a final concentration of either 40 nM or 1 mM enzymatic nucleic acid molecule, ie., enzymatic nucleic acid molecule excess. The reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05%) bromophenol blue and 0.05% xylene cyanol after which the sample is heated to 95 C for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel. Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact subsfrate and the cleavage products.

Example 9: Phase I/H Study of Repetitive Dosing of ANGIOZYME™ Targeting the VEGFRl (FLT-1) Receptor of VEGF

A ribozyme therapeutic agent ANGIOZYME™ (SEQ ID NO: 5977), was assessed by daily subcutaneous administration in a phase I/JJ trial for 31 patients with refractory solid tumors. Demographic information relating to patients enrolled in the study are shown in Table III. The primary study endpoint was to determine the safety and maximum tolerated dose of ANGIOZYME™. Secondary endpoints assessed ANGIOZYME™ pharmacokinetics and clinical response. Patients were treated at the following doses: 3 patients received doses of 10 mg/m^/day, 4 patients received 30 mg/m.2/day, 20 patients received 100 mg ^/day, and 4 patients received 300 mg/m^/day. All but one patient were dosed for a minimum of 29 consecutive days with 24-hour pharmacokinetic analyses on Day 1 and 29. Clinical response was assessed monthly. Results The data from 20 patients indicated that

ANGIOZYME™ was well tolerated, with no systemic adverse events. Figure 5 shows the plasma concentration profile of ANGIOZYME™ after a single subcutaneous dose of 10, 30, 100, or 300 mg/m². The pharmacokinetic parameters of ANGIOZYME™ after subcutaneous bolus administration are outlined in Table IV. An MTD (maximum tolerated dose) could not be established. One patient in the 300 mg/m²/d group experienced a grade 3 injection site reaction. Patients in the other groups experienced intermittent grade 1 and grade 2 injection site reactions with erythema and induration. No systemic or laboratory toxicities were observed. Pharmacokinetic analyses demonstrated dose-dependent plasma concentrations with good bioavailability (70-90%), tl/2 = 209-384 min, and no accumulation after repeated doses. To date, 17/28 (61%) of evaluable patients have had stable disease for periods of one to six months and two patients (nasopharyngeal squamous cell carcinoma and melanoma) had minor clinical responses. The patient with nasopharyngeal carcinoma demonstrated central tumor necrosis as indicated by MRI. The longest period of treatment thus far has been 8 months for two patients at 100 mg m²/d (breast, peritoneal mesothelioma).

Example 10: Down-regulation of VEGFRl gene expression to treat gynecologic neovascularization dependent conditions

One patient in the Phase I/π trial described in Example 19 was menstruating prior to enrollment in the ANGIOZYME™ monotherapy trial. After 1-2 months on trial, the patient's menstmal cycles ceased. The patient remained on trial for approximately 11 months and did not menstruate. The patient then went off the trial for about 4 months and the menstmal cycles resumed. Re-enrollment in the ANGIOZYME™ trial resulted in the patient's menstmal cycle stopping again. This clinical observation suggests that ANGIOZYME™ is interfering with the patient's menstrual cycle, perhaps by inhibiting neovascularization of uterine tissue. This data also suggests that ANGIOZYME™ has a direct effect on the endometrial tissue or an effect on LH FSH stimulation. These results suggest the freatment or control, using ANGIOZYME™ (SEQ ID NO: 5977) and/or other nucleic acid molecules of the instant invention, of various clinical targets and/or processes associated with female reproduction and gynecologic neovascularization, such as endometriosis, birth control, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), menopausal dysfunction, endometrial carcinoma or other condition associated with the expression of VEGFRl and/or VEGFR2 VEGF receptors.

Example 11: Down-regulation of VEGFRl in clinical setting

Twenty-seven of the patients enrolled in the Phase I/U trial described in Example 19 had day 1 (baseline) and day 43 (six-week) serum samples assayed for VEGFRl biomarker. VEGFRl levels were statistically different after six weeks of ANGIOZYME treatment (Figure 9). Although statistical testing involving all 27 patients showed statistical support for effects, not all patients presented with elevated levels of VEGF-R1. Since the effects of ANGIOZYME on VEGF-R1 may only be demonstrated when sufficient levels are present at baseline, a cutoff of 100 pg/mL was chosen and changes in this VEGF-R1 were re-analyzed. Ten of the 27 patients presented with baseline VEGF-R1 levels in excess of 100 pg/mL. For this subgroup VEGF-R1 levels were lower by 3-fold, p<.001. After six weeks of treatment the average (geometric mean) of VEGF-R1 decreased for this subgroup from 419 pg ml to 132pg/ml, p<.001. These results show that treatment with ANGIOZYME results in a statistically significant reduction in VEGFRl expression.

Example 22: In vivo inhibition of neovascularization in an ocular animal model by VEGF-R ribozymes. Summary of the Mouse Model: A mouse model of proliferative retinopathy (Aiello et al., 1995, Proc. Natl. Acad. Sci. USA 92: 10457-10461; Robinson et al, 1996, Proc. Natl. Acad. Sci. USA 93: 4851-4856; Pierce et al, 1996, Archives of Ophthalmology 114: 1219- 1228) in which neovascularization of the mouse retina is induced by exposure of 7-day old mice to 75% oxygen followed by a return to normal room air. The initial period in high oxygen causes an obliteration of developing blood vessels in the retina. Exposure to room air five days later is perceived as hypoxia by the now underperfused retina. The result is an immediate upregulation of VEGF mRNA and VEGF protein (between 6-12 hours) followed by an extensive retinal neovascularization that peaks in ~5 days. Although this model is more representative of retinopathy of prematurity than diabetic retinopathy, it is an accepted small animal model in which to study neovascular pathophysiology of the retina. In fact, intravitreal injection of certain antisense DNA constructs targeting VEGF mRNA have been found to be antiangiogenic in this model, as were soluble VEGF receptor chimeric proteins designed to bind VEGF in the vitreous humor (Aiello et al., 1995, Proc. Natl. Acad. Sci. USA 92: 10457-10461; Robinson et al, 1996, Proc. Natl. Acad. Sci. USA 93: 4851-4856; Pierce et al., 1996, Archives of Ophthalmology 114: 1219-1228).

Summary of experiment: The effect of an anti-KDR/Flk-1 ribozyme on the peak level of neovascularization was tested in the mouse model described above. As shown in Figure 10, P7 mice were removed from the hyperoxic chamber and the mice received two intraocular injections (P12 and P13) in the right eye of 10 μg RPI.4731, the anti- KDR/Flk-1 ribozyme. The left eye of each mouse was treated as a control and received intraocular injections of saline. Five days after being exposed to room air, neovascular nuclei in the retina of both eyes were counted. Data are presented in Figure 11. There was a significant decrease in retinal neovascularization (~40%) compared to the control, saline-injected eyes.

RPI.4731 sequence and chemical composition: 5 '-u_sa_sc_s a_sau ucU GAu Gag gcg aaa gcc Gaa Aag aca aB-3 ' (SEQ ID NO: 5978) where: uppercase G, A = ribonucleotides lowercase = 2'-OMe

U = 2'-C-allyl uridine B = inverted abasic nucleotide

S = phosphorothioate intemucleotide linkage

Indications

1) Tumor angiogenesis: Angiogenesis has been shown to be necessary for tumors to grow into pathological size (Folkman, 1971, PNAS 76, 5217-5221; Wellstein & Czubayko, 1996, Breast Cancer Res and Treatment 38, 109-119). In addition, it allows tumor cells to travel through the circulatory system during metastasis. Increased levels of gene expression of a number of angiogenic factors such as vascular endothelial growth factor (VEGF) have been reported in vascularized and edema-associated brain tumors (Berkman et al, 1993 J. Clini. Invest. 91, 153). A more direct demosfration of the role of VEGF in tumor angiogenesis was demonstrated by Jim Kim et al, 1993 Nature 362,841 wherein, monoclonal antibodies against VEGF were successfully used to inhibit the growth of rhabdomyosarcoma, glioblastoma multiforme cells in nude mice. Similarly, expression of a dominant negative mutated form of the flt-1 VEGF receptor inhibits vascularization induced by human glioblastoma cells in nude mice (Millauer et al, 1994, Nature 367, 576). Specific rumor/cancer types that can be targeted using the nucleic acid molecules of the invention include but are not limited to the tumor/cancer types described under Diagnosis in Table III.

2) Ocular diseases: Neovascularization has been shown to cause or exacerbate ocular diseases including but not limited to, macular degeneration, neovascular glaucoma, diabetic retinopathy, myopic degeneration, and trachoma (Norrby, 1997, APMIS 105, 417-437). Aiello et al, 1994 New Engl. J. Med. 331, 1480, showed that the ocular fluid, of a majority of patients suffering from diabetic retinopathy and other retinal disorders, contains a high concentration of VEGF. Miller et al, 1994 Am. J. Paihol 145, 574, reported elevated levels of VEGF mRNA in patients suffering from retinal ischemia. These observations support a direct role for VEGF in ocular diseases. Other factors including those that stimulate VEGF synthesis may also contribute to these indications.

3) Dermatological Disorders: Many indications have been identified which may by angiogenesis dependent including but not limited to psoriasis, verruca vulgaris, angiofibroma of tuberous sclerosis, pot-wine stains, Sturge Weber syndrome, Kippel-Trenaunay-Weber syndrome, and Osier- Weber-Rendu syndrome (Norrby, supra). Intradermal injection of the angiogenic factor b-FGF demonstrated angiogenesis in nude mice (Weckbecker et al., 1992, Angiogenesis: Key principles-Science-Technology-Medicine, ed R. Steiner) Detmar et al, 1994 J. Exp. Med. 180, 1141 reported that VEGF and its receptors were over-expressed in psoriatic skin and psoriatic dermal microvessels, suggesting that VEGF plays a significant role in psoriasis.

4) Rheumatoid arthritis: Immunohistochemistry and in situ hybridization studies on tissues from the joints of patients suffering from rheumatoid arthritis show an increased level of VEGF and its receptors (Fava et al, 1994 J. Exp. Med. 180, 341). Additionally, Koch et al, 1994 J. Immunol. 152, 4149, found that VEGF-specific antibodies were able to significantly reduce the mitogenic activity of synovial tissues from patients suffering from rheumatoid arthritis. These observations support a direct role for VEGF in rheumatoid arthritis. Other angiogenic factors including those of the present invention may also be involved in arthritis.

5) Endometriosis: Various studies indicate that VEGF is directly implicated in endometriosis. hi one study, VEGF concentrations measured by ELISA in peritoneal fluid were found to be significantly higher in women with endometriosis than in women without endometriosis (24.1 ± 15 ng/ml vs 13.3 ± 7.2 ng/ml in normals), hi patients with endometriosis, higher concentrations of VEGF were detected in the proliferative phase of the menstmal cycle (33 + 13 ng/ml) compared to the secretory phase (10.7 + 5 ng/ml). The cyclic variation was not noted in fluid from normal patients (McLaren et al, 1996, Human Reprod. 11, 220-223). h another study, women with moderate to severe endometriosis had significantly higher concentrations of peritoneal fluid VEGF than women without endometriosis. There was a positive correlation between the severity of endometriosis and the concentration of VEGF in peritoneal fluid. In human endometrial biopsies, VEGF expression increased relative to the early proliferative phase approximately 1.6-, 2-, and 3.6-fold in midproliferative, late proliferative, and secretory endometrium (Shifren et al, 1996, J. Clin. Endocrinol Metab. 81, 3112-3118).

hi a third study, VEGF-positive staining of human ectopic endometrium was shown to be localized to macrophages (double immunofluorescent staining with CD 14 marker). Peritoneal fluid macrophages demonstrated VEGF staining in women with and without endometriosis. However, increased activation of macrophages (acid phosphatatse activity) was demonstrated in fluid from women with endometriosis compared with controls. Peritoneal fluid macrophage conditioned media from patients with endometriosis resulted in significantly increased cell proliferation ([³H] thymidine incorporation) in HUVEC cells compared to controls. The percentage of peritoneal fluid macrophages with VEGFR2 mRNA was higher during the secretory phase, and significantly higher in fluid from women with endometriosis (80 ± 15%) compared with controls (32 ± 20%). Flt-rnRNA was detected in peritoneal fluid macrophages from women with and without endometriosis, but there was no difference between the groups or any evidence of cyclic dependence (McLaren et al, 1996, J. Clin. Invest. 98, 482-489).

hi the early proliferative phase of the menstmal cycle, VEGF has been found to be expressed in secretory columnar epithelium (estrogen-responsive) lining both the oviducts and the uterus in female mice. During the secretory phase, VEGF expression was shown to have shifted to the underlying stroma composing the functional endometrium. In addition to examining the endometrium, neovascularization of ovarian follicles and the corpus luteum, as well as angiogenesis in embryonic implantation sites have been analyzed. For these processes, VEGF was expressed in spatial and temporal proximity to forming vasculature (Shweiki et al, 1993, J. Clin. Invest. 91, 2235-2243).

The present body of knowledge in VEGFRl and/or VEGFR2 research indicates the need for methods to assay VEGFRl and/or VEGFR2 activity and for compounds that can regulate VEGFRl and/or VEGFR2 expression for research, diagnostic, and therapeutic use. As described herein, the nucleic acid molecules of the present invention can be used in assays to diagnose disease state related of VEGF, VEGFRl and/or VEGFR2 levels, hi addition, the nucleic acid molecules can be used to treat disease state related to VEGF and/or VEGFr, such as VEGFRl and or VEGFR2 levels.

Particular processes, diseases, or conditions that can be associated with VEGFRl and/or VEGFR2 levels include, but are not limited to, gynecologic neovascularization, such as endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstmal cycles, ovulation, premenstrual syndrome (PMS), menopausal dysfunction, other diseases and conditions discussed herein, and other diseases or conditions that are related to or respond to the levels of VEGF and/or VEGFr, such as VEGFRl and or VEGFR2, in a cell or tissue, alone or in combination with other therapies

The use of GnRH (gonadotropin releasing hormone) agonists, Lupron Depot (Leuprolide Acetate), Synarel (naferalin acetate), Zolodex (goserelin acetate), Suprefact (buserelin acetate), Danazol, or oral contraceptives including, but not limited to, Depo-Provera or Provera (medroxyprogesterone acetate), or any other estrogen/progesterone contraceptive, are all non-limiting examples of compounds and methods that can be combined with or used in conjunction with the nucleic acid molecules of the instant invention. Various chemotherapies can be readily combined with nucleic acid molecules of the invention for the treatment of endometrial carcinoma. Common chemotherapies that can be combined with nucleic acid molecules of the instant invention include various combinations of cytotoxic drags to kill the cancer cells. These drugs include but are not limited to paclitaxel (Taxol), docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, vinorelbine etc. Those skilled in the art will recognize that other drug compounds and therapies can be readily combined with the nucleic acid molecules of the instant invention and are hence within the scope of the instant invention.

Animal Models

There are several animal models in which the anti-angiogenesis effect of nucleic acids of the present invention, such as ribozymes, directed against VEGF-R mRNAs can be tested. Typically, a comeal model has been used to study angiogenesis in rat and rabbit since recraitment of vessels can easily be followed in this normally avascular tissue (Pandey et al, 1995 Science 268: 567-569). i these models, a small Teflon or Hydron disk prefreated with an angiogenesis factor (e.g. bFGF or VEGF) is inserted into a pocket surgically created in the cornea. Angiogenesis is monitored 3 to 5 days later. Ribozymes directed against VEGF-R mRNAs would be delivered in the disk as well, or dropwise to the eye over the time course of the experiment. In another eye model, hypoxia has been shown to cause both increased expression of VEGF and neovascularization in the retina (Pierce et al, 1995 Proc. Natl. Acad. Sci. USA. 92: 905-909; Shweiki et al, 1992 J. Clin. Invest. 91: 2235-2243).

hi human glioblastomas, it has been shown that VEGF is at least partially responsible for tumor angiogenesis (Plate et al, 1992 Nature 359, 845). Animal models have been developed in which glioblastoma cells are implanted subcutaneously into nude mice and the progress of tumor growth and angiogenesism is studied (Kim et al, 1993 supra; Millauer et al, 1994 supra).

Another animal model that addresses neovascularization involves Matrigel, an extract of basement membrane that becomes a solid gel when injected subcutaneously (Passaniti et al, 1992 Lab. Invest. 67: 519-528). When the Matrigel is supplemented with angiogenesis factors such as VEGF, vessels grow into the Matrigel over a period of 3 to 5 days and angiogenesis can be assessed. Ribozymes directed against VEGF-R mRNAs can be delivered in the Matrigel to assess anti-angiogesis effect.

Several animal models exist for screening of anti-angiogenic agents. These include comeal vessel formation following comeal injury (Burger et al, 1985 Cornea 4: 35-41;

Lepri, et al, 1994 J. Ocular Pharmacol. 10: 273-280; Ormerod et al, 1990 Am. J. Pathol

137: 1243-1252) or infracorneal growth factor implant (Grant et al, 1993 Diabetologia 36:

282-291; Pandey et al. 1995 supra; Zieche et al, 1992 Lab. Invest. 67: 711-715), vessel growth into Matrigel matrix containing growth factors (Passaniti et al, 1992 supra), female reproductive organ neovascularization following hormonal manipulation (Shweiki et al, 1993 Clin. Invest. 91: 2235-2243), several models involving inhibition of tumor growth in highly vascularized solid tumors (O'Reilly et al, 1994 Cell 79: 315-328; Senger et al, 1993 Cancer and Metas. Rev. 12: 303-324; Takahasi et al, 1994 Cancer Res. 54: 4233-4237; Kim et al, 1993 supra), and transient hypoxia-induced neovascularization in the mouse retina (Pierce et al, 1995 Proc. Natl. Acad. Sci. USA. 92: 905-909).

The cornea model, described in Pandey et al. supra, is the most common and well characterized anti-angiogenic agent efficacy screening model. This model involves an avascular tissue into which vessels are recruited by a stimulating agent (growth factor, thermal or alkalai bum, endotoxin). The comeal model utilizes the intrastromal comeal implantation of a Teflon pellet soaked in a VEGF-Hydron solution to recruit blood vessels toward the pellet which can be quantitated using standard microscopic and image analysis techniques. To evaluate their anti-angiogenic efficacy, ribozymes are applied topically to the eye or bound within Hydron on the Teflon pellet itself. This avascular cornea as well as the Matrigel (see below) provide for low background assays. While the comeal model has been performed extensively in the rabbit, studies in the rat have also been conducted.

The mouse model (Passaniti et al., supra) is a non-tissue model which utilizes Matrigel, an extract of basement membrane (Kleinman et al., 1986) or Millipore® filter disk, which can be impregnated with growth factors and anti-angiogenic agents in a liquid form prior to injection. Upon subcutaneous administration at body temperature, the Matrigel or Millipore® filter disk forms a solid implant. VEGF embedded in the Matrigel or Millipore® filter disk would be used to recruit vessels within the matrix of the Matrigel or Millipore® filter disk which can be processed histologically for endothelial cell specific vWF (factor Vm antigen) immunohistochemistry, Trichrome-Masson stain, or hemoglobin content. Like the comea, the Matrigel or Millipore® filter disk are avascular; however, it is not tissue. In the Matrigel or Millipore® filter disk model, ribozymes are administered within the matrix of the Matrigel or Millipore® filter disk to test their anti-angiogenic efficacy. Thus, delivery issues in this model, as with delivery of ribozymes by Hydron- coated Teflon pellets in the rat comea model, are minimized due to the homogeneous presence of the ribozyme within the respective matrix.

These models offer a distinct advantage over several other angiogenic models listed previously. The ability to use VEGF as a pro-angiogenic stimulus in both models is highly desirable since ribozymes target only VEGFr mRNA. In other words, the involvement of other non-specific types of stimuli in the comea and Matrigel models is not advantageous from the standpoint of understanding the pharmacologic mechanism by which the anti- VEGFr mRNA ribozymes produce their effects. In addition, the models allow for testing the specificity of the anti- VEGFr mRNA ribozymes by using either aFGF or bFGF as a pro- angiogenic factor. Vessel recruitment using FGF should not be affected in either model by anti- VEGFr mRNA ribozymes. Other models of angiogenesis, including vessel formation in the female reproductive system using hormonal manipulation (Shweiki et al, 1993 supra); a variety of vascular solid tumor models which involve indirect correlations with angiogenesis (O'Reilly et al, 1994 supra; Senger et al, 1993 supra; Takahasi et al, 1994 supra; Kim et al, 1993 supra); and retinal neovascularization following transient hypoxia (Pierce et al, 1995 supra), were not selected for efficacy screening due to their non-specific nature, although they can be useful models due to a demonstrated correlation between VEGF and angiogenesis.

Other model systems to study tumor angiogenesis is reviewed by Folkman, 1985 Adv. Cancer. Res.. 43, 175.

Use of murine models

For a typical systemic study involving 10 mice (20 g each) per dose group, 5 doses (1,

3, 10, 30 and 100 mg/kg daily over 14 days continuous administration), approximately 400 mg of ribozyme, formulated in saline would be used. A similar study in young adult rats (200 g) would require over 4 g. Parallel pharmacokinetic studies involve the use of similar quantities of ribozymes further justifying the use of murine models.

Ribozymes and Lewis lung carcinoma and B-16 melanoma murine models

Identifying a common animal model for systemic efficacy testing of ribozymes is an efficient way of screening ribozymes for systemic efficacy.

The Lewis lung carcinoma and B-16 murine melanoma models are well accepted models of primary and metastatic cancer and are used for initial screening of anti-cancer agents. These murine models are not dependent upon the use of immunodeficient mice, are relatively inexpensive, and minimize housing concerns. Both the Lewis lung and B-16 melanoma models involve subcutaneous implantation of approximately 10⁶ tumor cells from metastatically aggressive tumor cell lines (Lewis lung lines 3LL or D122, LLc-LN7; B-16- BL6 melanoma) in C57BL/6J mice. Alternatively, the Lewis lung model can be produced by the surgical implantation of tumor spheres (approximately 0.8 mm in diameter). Metastasis also can be modeled by injecting the tumor cells directly intraveneously. In the Lewis lung model, microscopic metastases can be observed approximately 14 days following implantation with quantifiable macroscopic metastatic tumors developing within 21-25 days. The B-16 melanoma exhibits a similar time course with tumor neovascularization beginning 4 days following implantation. Since both primary and metastatic tumors exist in these models after 21-25 days in the same animal, multiple measurements can be taken as indices of efficacy. Primary tumor volume and growth latency as well as the number of micro- and macroscopic metastatic lung foci or number of animals exhibiting metastases can be quantitated. The percent increase in lifespan can also be measured. Thus, these models provide suitable primary efficacy assays for screening systemically administered ribozymes/ribozyme formulations.

hi the Lewis lung and B-16 melanoma models, systemic pharmacotherapy with a wide variety of agents usually begins 1-7 days following tumor implantation inoculation with either continuous or multiple administration regimens. Concurrent pharmacokinetic studies can be performed to determine whether sufficient tissue levels of ribozymes can be achieved for pharmacodynamic effect to be expected. Furthermore, primary tumors and secondary lung metastases can be removed and subjected to a variety of in vitro studies (i.e. target RNA reduction).

Flt-1, KDR and/or flk-1 protein levels can be measured clinically or experimentally by FACS analysis. Flt-1, KDR and or flk-1 encoded mRNA levels can be assessed by Northern analysis, RNase-protection, primer extension analysis and/or quantitative RT-PCR. Ribozymes that block flt-1, KDR and/or flk-1 protein encoding mRNAs and therefore result in decreased levels of flt-1, KDR and or flk-1 activity by more than 20% in vitro can be identified.

Ribozymes and/or genes encoding them are delivered by either free' delivery, liposome delivery, cationic lipid delivery, adeno-associated vims vector delivery, adenovirus vector delivery, retrovirus vector delivery or plasmid vector delivery in these animal model experiments (see above).

Subjects can be treated by locally administering nucleic acids targeted against VEGF-R by direct injection. Routes of administration include, but are not limited to, intravascular, intramuscular, subcutaneous, intraarticular, aerosol inhalation, oral (tablet, capsule or pill form), topical, systemic, ocular, intraperitoneal and/or intrathecal delivery. Surgically induced models of endometriosis have been developed in rats, mice, and rabbits. Non-human primates demonstrate spontaneous endometriosis, but surgical induction can also be used, hi addition to the surgical technique, cycle monitoring can be performed by daily vaginal cytology in primates. For all of the surgically induced models of endometriosis, the following general procedure is used. An initial laparotomy is performed to implant tissue from a donor animal. A portion of one uterine hom (or one complete hom in the case of mice) is removed. The endometrium of this piece of uterus is separated from the myometrium and cut into small segments (4-10 mm2). Segments (approximately 3) are sutured to various locations within the abdominal cavity (peritoneum, intestinal mesentery vessels, uterus, broad ligament). Cummings and Metcalf (1996) attached whole segments of mouse uterus without separating the endometrium from the myometrium. Implants are allowed to grow for 3-6 weeks. A second laparotomy is sometimes performed to verify development of endometriosis-like foci (vascularization and cysts filled with clear fluid). This second laparotomy was done in the studies by Quereda et al, (1996) and Stoeckemann et al, (1995). After 3-6 weeks post-surgery and/or following visualization of endometriosis, drug treatment is initiated and continued for a prescribed period of time. At the termination of these studies, animals are euthanized. Endpoints include, but are not limited to, changes in the surface area of the implants and tissue mass of the ectopic endometrial implants (see for example Brogniez et al, 1995, Human Reprod. 10, 927-931; Cummings et al, 1996, Tox. Appl Pharm. 138, 131-139; Cummings and Metcalf, 1996, Proc. Soc. Exp. Biol. Med. 212, 332- 337; D'Hooghe et al, 1996, Fertility and Sterility. 66, 809-813; Quereda et al, 1996, Eur. J. Obstet. Gynecol Rep. Biol. 67, 35-40; and Stoeckemann et al, 1995, Human Reprod. 10, 3264-3271).

Combination therapies

Gemcytabine and cyclophosphamide are non-limiting examples of chemotherapeutic agents that can be combined with or used in conjunction with the nucleic acid molecules (e.g. ribozymes and antisense molecules) of the instant invention. Those skilled in the art will recognize that other anti-angiogenic and/or anti-cancer compounds and therapies can be similarly be readily combined with the nucleic acid molecules of the instant invention (e.g. ribozymes and antisense molecules) and are hence within the scope of the instant invention. Such compounds and therapies are well known in the art (see for example Cancer: Principles and Pranctice of Oncology, Volumes 1 and 2, eds Devita, V.T., Hellman, S., and Rosenberg, S.A., J.B. Lippincott Company, Philadelphia, USA; incorporated herein by reference) and include, without limitations, folates, antifolates, pyrimidine analogs, fluoropyrimidines, purine analogs, adenosine analogs, topoisomerase I inhibitors, anthrapyrazoles, retinoids, antibiotics, anthacyclins, platinum analogs, alkylating agents, nifrosoureas, plant derived compounds such as vinca alkaloids, epipodophyllotoxins, tyrosine kinase inhibitors, taxols, radiation therapy, surgery, nutritional supplements, gene therapy, radiotherapy, for example 3D-CRT, immunotoxin therapy, for example ricin, and monoclonal antibodies. Specific examples of chemotherapeutic compounds than can be combined with or used in conjuction with the nucleic acid molecules of the invention include but are not limited to Paclitaxel; Docetaxel; Methotrexate; Doxorubin; Edatrexate; Vinorelbine; Tomaxifen; Leucovorin; 5- fluoro uridine (5-FU); notecan (CAMPTOSAR® or CPT-11 or Camptothecin-11 or Campto); Cisplatin; Carboplatin; Amsacrine; Cytarabine; Bleomycin; Mitomycin C; Dactinomycin; Mithramycin; Hexamethylmelamine; Dacarbazine; L-asperginase; Nitrogen mustard; Melphalan, Chlorambucil; Busulfan; Ifosfamide; 4-hydroperoxycyclophosphamide, Thiotepa; Tamoxifen, Herceptin; IMC C225; ABX-EGF: and combinations thereof.

Diagnostic uses

The nucleic acid molecules of this invention (e.g., enzymatic nucleic acid molecules) can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of VEGF and/or VEGFr, such as VEGFRl and/or VEGFR2 RNA in a cell. The close relationship between enzymatic nucleic acid molecule activity and the structure of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional structure of the target RNA. By using multiple enzymatic nucleic acid molecules described in this invention, one can map nucleotide changes which are important to RNA structure and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets can be defined as important mediators of the disease. These experiments can lead to better treatment of the disease progression by affording the possibility of combinational therapies (e.g., multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules). Other in vitro uses of enzymatic nucleic acid molecules of this invention are well known in the art, and include detection of the presence of mRNAs associated with VEGF, VEGFRl and/or VEGFR2-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with an enzymatic nucleic acid molecule using standard methodology. hi a specific example, enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay. The first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the "non-targeted" RNA species. The cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions. The presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype (i.e., VEGFRl and or VEGFR2) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost of the initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively. The use of enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is described, for example, in Usman et al, US Patent Application No. 09/877,526, George et al, US Patent Nos. 5,834,186 and 5,741,679, Shih et al, US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al, International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al, US Patent Application Serial No. 09/205,520.

Additional Uses

Uses of sequence-specific enzymatic nucleic acid molecules of the instant invention can have many of the same applications for the study of RNA that DNA restriction endonucleases have for the study of DNA (Nathans et al, 1975 Ann. Rev. Biochem. 44:273). For example, the pattern of restriction fragments can be used to establish sequence relationships between two related RNAs, and large RNAs can be specifically cleaved to fragments of a size more useful for study. The ability to engineer sequence specificity of the enzymatic nucleic acid molecule is ideal for cleavage of RNAs of unknown sequence. Applicant has described the use of nucleic acid molecules to down-regulate gene expression of target genes in bacterial, microbial, fungal, viral, and eukaryotic systems including plant, or mammalian cells.

All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incorporated by reference to the same extent as if each reference had been incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of and "consisting of may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of hmitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims. hi addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.

Other embodiments are within the following claims.

TABLE I

Characteristics of Ribozymes

Group I Introns

Size: -200 to >1000 nucleotides.

Requires a U in the target sequence immediately 5' of the cleavage site.

Binds 4-6 nucleotides at 5' side of cleavage site.

Over 75 known members of this class. Found in Tetrahymena thermophila rRNA, fungal mitochondria, chloroplasts, phage T4, blue-green algae, and others.

RNAseP RNA (M1 RNA)

Size: -290 to 400 nucleotides.

RNA portion of a ribonucleoprotein enzyme. Cleaves tRNA precursors to form mature tRNA.

Roughly 10 known members of this group all are bacterial in origin.

Hammerhead Ribozyme

Size: -13 to 40 nucleotides.

Requires the target sequence UH immediately 5' of the cleavage site.

Binds a variable number of nucleotides on both sides of the cleavage site.

14 known members of this class. Found in a number of plant pathogens (virusoids) that use RNA as the infectious agent (Figure 1 and 2)

Hairpin Ribozyme

Size: -50 nucleotides.

Requires the target sequence GUC immediately 3' of the cleavage site.

Binds 4-6 nucleotides at 5' side of the cleavage site and a variable number to the 3' side of the cleavage site.

Only 3 known member of this class. Found in three plant pathogen

(satellite RNAs of the tobacco ringspot virus, arabis mosaic virus and chicory yellow mottle virus) which uses RNA as the infectious agent (Figure 3).

Hepatitis Delta Virus (HDV) Ribozyme

Size: 50 - 60 nucleotides (at present).

Sequence requirements not fully determined.

Binding sites and structural requirements not fully determined, although no sequences 5' of cleavage site are required.

Only 1 known member of this class. Found in human HDV (Figure

4).

Neurospora VS RNA Ribozyme Size: -144 nucleotides (at present)

Cleavage of target RNAs recently demonstrated.

Sequence requirements not fully determined.

Binding sites and structural requirements not fully determined. Only

1 known member of this class. Found in Neurospora VS RNA

(Figure 5).

Table II:

A. 2.5 μmol Synthesis Cycle ABI 394 Instrument

Reagent Equivalents Amount Wait Time* DNA Wait Time* 2'- Wait Time* O-methyl RNA

Phosphoramidites 6.5 163 μL 45 sec 2.5 min 7.5 min S-Ethyl Tetrazole 23.8 238 μL 45 sec 2.5 min 7.5 min Acetic Anhydride 100 233 μL 5 sec 5 sec 5 sec Λ/-Methyl Imidazole 186 233 μL 5 sec 5 sec 5 sec TCA 176 2.3 mL 21 sec 21 sec 21 sec Iodine 11.2 1.7 mL 45 sec 45 sec 45 sec Beaucage 12.9 645 μL 100 sec 300 sec 300 sec Acetonitrile NA 6.67 mL NA NA NA o

B. 0.2 μmol Synthesis Cycle ABI 394 Instrument

Phosphoramidites 15 31 μL 45 sec 233 sec 465 sec S-Ethyl Tetrazole 38.7 31 μL 45 sec 233 min 465 sec Acetic Anhydride 655 124 μL 5 sec 5 sec 5 sec A/-Methyl Imidazole 1245 124 μL 5 sec 5 sec 5 sec TCA 700 732 μL 10 sec 10 sec 10 sec Iodine 20.6 244 μL 15 sec 15 sec 15 sec

Beaucage 7.7 232 μL 100 sec 300 sec 300 sec Acetonitrile NA 2.64 mL NA NA NA

C. 0.2 μmol Synthesis Cycle 96 well Instrument

Reagent Equivalents Amount Wait Time* Wait Time* 2'-0- Wait Time* Ribo

DNA/2'-0-methyl/Ribo DNA/2'-0-methyl/Ribo DNA methyl

Phosphoramidites 22/33/66 40/60/120 μL 60 sec 180 sec 360sec

S-Ethyl Tetrazole 70/105/210 40/60/120 μL 60 sec 180 min 360 sec

Acetic Anhydride 265/265/265 50/50/50 μL 10 sec 10 sec 10 sec

Λ/-Methyl Imidazole 502/502/502 50/50/50 μL 10 sec 10 sec 10 sec

TCA 238/475/475 250/500/500 μL 15 sec 15 sec 15 sec

Iodine 6.8/6.8/6.8 80/80/80 μL 30 sec 30 sec 30 sec

Beaucage 34/51/51 80/120/120 100 sec 200 sec 200 sec VO

Acetonitrile NA 1150/1150/1150 μL NA NA NA

^: Wait time does not include contact time during delivery.

Table III: Patient Demographics

One patient taken off study due to progressive disease. Allowed to resume ANGIOZYME on a compassionate basis.

As of September 1, 2001, all patients were off study. (Although one patient resumed treatment per above note) Table IV Pharmacokinetic parameters of ANGIOZYME after bolus subcutaneous administration.

Table V: Human FLT DNAzyme and Substrate Sequence

Pos Substrate SeqlD DNAzyme SeqlD

No No

17 UCCUCUCG G CUCCUCCC 1 GGGAGGAG GGCTAGCTACAACGA CGAGAGGA 1703

28 CCUCCCCG G CAGCGGCG 2 CGCCGCTG GGCTAGCTACAACGA CGGGGAGG 1704

31 CCCCGGCA G CGGCGGCG 3 CGCCGCCG GGCTAGCTACAACGA TGCCGGGG 1705

34 CGGCAGCG G CGGCGGCU 4 AGCCGCCG GGCTAGCTACAACGA CGCTGCCG 1706

37 CAGCGGCG G CGGCUCGG 5 CCGAGCCG GGCTAGCTACAACGA CGCCGCTG 1707

40 CGGCGGCG G CUCGGAGC 6 GCTCCGAG GGCTAGCTACAACGA CGCCGCCG 1708

47 GGCUCGGA G CGGGCUCC 7 GGAGCCCG GGCTAGCTACAACGA TCCGAGCC 1709

51 CGGAGCGG G CUCCGGGG 8 CCCCGGAG GGCTAGCTACAACGA CCGCTCCG 1710

59 GCUCCGGG G CϋCGGGUG 9 CACCCGAG GGCTAGCTACAACGA CCCGGAGC 1711

65 GGGCUCGG G UGCAGCGG 10 CCGCTGCA GGCTAGCTACAACGA CCGAGCCC 1712

67 GCUCGGGU G CAGCGGCC 11 GGCCGCTG GGCTAGCTACAACGA ACCCGAGC 1713

70 CGGGUGCA G CGGCCAGC 12 GCTGGCCG GGCTAGCTACAACGA TGCACCCG 1714

73 GUGCAGCG G CCAGCGGG 13 CCCGCTGG GGCTAGCTACAACGA CGCTGCAC 1715

77 AGCGGCCA G CGGGCCUG 14 CAGGCCCG GGCTAGCTACAACGA TGGCCGCT 1716

81 GCCAGCGG G CCUGGCGG 15 CCGCCAGG GGCTAGCTACAACGA CCGCTGGC 1717

86 CGGGCCUG G CGGCGAGG 16 CCTCGCCG GGCTAGCTACAACGA CAGGCCCG 1718

89 GCCUGGCG G CGAGGAUU 17 AATCCTCG GGCTAGCTACAACGA CGCCAGGC 1719

95 CGGCGAGG A UUACCCGG 18 CCGGGTAA GGCTAGCTACAACGA CCTCGCCG 1720

98 CGAGGAUU A CCCGGGGA 19 TCCCCGGG GGCTAGCTACAACGA AATCCTCG 1721

108 CCGGGGAA G UGGUUGUC 20 GACAACCA GGCTAGCTACAACGA TTCCCCGG 1722

111 GGGAAGUG G UUGUCUCC 21 GGAGACAA GGCTAGCTACAACGA CACTTCCC 1723

114 AAGUGGUU G UCUCCUGG 22 CCAGGAGA GGCTAGCTACAACGA AACCACTT 1724

122 GUCUCCUG G CUGGAGCC 23 GGCTCCAG GGCTAGCTACAACGA CAGGAGAC 1725

128 UGGCUGGA G CCGCGAGA 24 TCTCGCGG GGCTAGCTACAACGA TCCAGCCA 1726

131 CUGGAGCC G CGAGACGG 25 CCGTCTCG GGCTAGCTACAACGA GGCTCCAG 1727

136 GCCGCGAG A CGGGCGCU 26 AGCGCCCG GGCTAGCTACAACGA CTCGCGGC 1728

140 CGAGACGG G CGCUCAGG 27 CCTGAGCG GGCTAGCTACAACGA CCGTCTCG 1729

142 AGACGGGC G CUCAGGGC 28 GCCCTGAG GGCTAGCTACAACGA GCCCGTCT 1730

149 CGCUCAGG G CGCGGGGC 29 GCCCCGCG GGCTAGCTACAACGA CCTGAGCG 1731

151 CUCAGGGC G CGGGGCCG 30 CGGCCCCG GGCTAGCTACAACGA GCCCTGAG 1732

156 GGCGCGGG G CCGGCGGC 31 GCCGCCGG GGCTAGCTACAACGA CCCGCGCC 1733

160 CGGGGCCG G CGGCGGCG 32 CGCCGCCG GGCTAGCTACAACGA CGGCCCCG 1734

163 GGCCGGCG G CGGCGAAC 33 GTTCGCCG GGCTAGCTACAACGA CGCCGGCC 1735

166 CGGCGGCG G CGAACGAG 34 CTCGTTCG GGCTAGCTACAACGA CGCCGCCG 1736

170 GGCGGCGA A CGAGAGGA 35 TCCTCTCG GGCTAGCTACAACGA TCGCCGCC 1737

178 ACGAGAGG A CGGACUCU 36 AGAGTCCG GGCTAGCTACAACGA CCTCTCGT 1738

182 GAGGACGG A CUCUGGCG 37 CGCCAGAG GGCTAGCTACAACGA CCGTCCTC 1739

188 GGACUCUG G CGGCCGGG 38 CCCGGCCG GGCTAGCTACAACGA CAGAGTCC 1740

191 CUCUGGCG G CCGGGUCG 39 CGACCCGG GGCTAGCTACAACGA CGCCAGAG 1741

196 GCGGCCGG G UCGUUGGC 40 GCCAACGA GGCTAGCTACAACGA CCGGCCGC 1742

199 GCCGGGUC G UUGGCCGG 41 CCGGCCAA GGCTAGCTACAACGA GACCCGGC 1743

203 GGUCGUUG G CCGGGGGA 42 TCCCCCGG GGCTAGCTACAACGA CAACGACC 1744

212 CCGGGGGA G CGCGGGCA 43 TGCCCGCG GGCTAGCTACAACGA TCCCCCGG 1745

214 GGGGGAGC G CGGGCACC 44 GGTGCCCG GGCTAGCTACAACGA GCTCCCCC 1746

218 GAGCGCGG G CACCGGGC 45 GCCCGGTG GGCTAGCTACAACGA CCGCGCTC 1747

220 GCGCGGGC A CCGGGCGA 46 TCGCCCGG GGCTAGCTACAACGA GCCCGCGC 1748

225 GGCACCGG G CGAGCAGG 47 CCTGCTCG GGCTAGCTACAACGA CCGGTGCC 1749

229 CCGGGCGA G CAGGCCGC 48 GCGGCCTG GGCTAGCTACAACGA TCGCCCGG 1750 233 GCGAGCAG G CCGCGUCG 49 CGACGCGG GGCTAGCTACAACGA CTGCTCGC 1751

236 AGCAGGCC G CGUCGCGC 50 GCGCGACG GGCTAGCTACAACGA GGCCTGCT 1752

238 CAGGCCGC G UCGCGCUC 51 GAGCGCGA GGCTAGCTACAACGA GCGGCCTG 1753

241 GCCGCGUC G CGCUCACC 52 GGTGAGCG GGCTAGCTACAACGA GACGCGGC 1754

243 CGCGUCGC G CUCACCAU 53 ATGGTGAG GGCTAGCTACAACGA GCGACGCG 1755

247 UCGCGCUC A CCAUGGUC 54 GACCATGG GGCTAGCTACAACGA GAGCGCGA 1756

250 CGCUCACC A UGGUCAGC 55 GCTGACCA GGCTAGCTACAACGA GGTGAGCG 1757

253 UCACCAUG G UCAGCUAC 56 GTAGCTGA GGCTAGCTACAACGA CATGGTGA 1758

257 CAUGGUCA G CUACUGGG 57 CCCAGTAG GGCTAGCTACAACGA TGACCATG 1759

260 GGUCAGCU A CUGGGACA 58 TGTCCCAG GGCTAGCTACAACGA AGCTGACC 1760

266 CUACUGGG A CACCGGGG 59 CCCCGGTG GGCTAGCTACAACGA CCCAGTAG 1761

268 ACUGGGAC A CCGGGGUC 60 GACCCCGG GGCTAGCTACAACGA GTCCCAGT 1762

274 ACACCGGG G UCCUGCUG 61 CAGCAGGA GGCTAGCTACAACGA CCCGGTGT 1763

279 GGGGUCCU G CUGUGCGC 62 GCGCACAG GGCTAGCTACAACGA AGGACCCC 1764

282 GUCCUGCU G UGCGCGCU 63 AGCGCGCA GGCTAGCTACAACGA AGCAGGAC 1765

284 CCUGCUGU G CGCGCUGC 64 GCAGCGCG GGCTAGCTACAACGA ACAGCAGG 1766

286 UGCUGUGC G CGCUGCUC 65 GAGCAGCG GGCTAGCTACAACGA GCACAGCA 1767

288 CUGUGCGC G CUGCUCAG 66 CTGAGCAG GGCTAGCTACAACGA GCGCACAG 1768

291 UGCGCGCU G CUCAGCUG 67 CAGCTGAG GGCTAGCTACAACGA AGCGCGCA 1769

296 GCUGCUCA G CUGUCUGC 68 GCAGACAG GGCTAGCTACAACGA TGAGCAGC 1770

299 GCUCAGCU G UCUGCUUC 69 GAAGCAGA GGCTAGCTACAACGA AGCTGAGC 1771

303 AGCUGUCU G CUUCUCAC 70 GTGAGAAG GGCTAGCTACAACGA AGACAGCT 1772

310 UGCUUCUC A CAGGAUCU 71 AGATCCTG GGCTAGCTACAACGA GAGAAGCA 1773

315 CUCACAGG A UCUAGUUC 72 GAACTAGA GGCTAGCTACAACGA CCTGTGAG 1774

320 AGGAUCUA G UUCAGGUU 73 AACCTGAA GGCTAGCTACAACGA TAGATCCT 1775

326 UAGUUCAG G UUCAAAAU 74 ATTTTGAA GGCTAGCTACAACGA CTGAACTA 1776

333 GGUUCAAA A UUAAAAGA 75 TCTTTTAA GGCTAGCTACAACGA TTTGAACC 1777

341 AUUAAAAG A UCCUGAAC 76 GTTCAGGA GGCTAGCTACAACGA CTTTTAAT 1778

348 GAUCCUGA A CUGAGUUU 77 AAACTCAG GGCTAGCTACAACGA TCAGGATC 1779

353 UGAACUGA G UUUAAAAG 78 CTTTTAAA GGCTAGCTACAACGA TCAGTTCA 1780

362 UUUAAAAG G CACCCAGC 79 GCTGGGTG GGCTAGCTACAACGA CTTTTAAA 1781

364 UAAAAGGC A CCCAGCAC 80 GTGCTGGG GGCTAGCTACAACGA GCCTTTTA 1782

369 GGCACCCA G CACAUCAU 81 ATGATGTG GGCTAGCTACAACGA TGGGTGCC 1783

371 CACCCAGC A CAUCAUGC 82 GCATGATG GGCTAGCTACAACGA GCTGGGTG 1784

373 CCCAGCAC A UCAUGCAA 83 TTGCATGA GGCTAGCTACAACGA GTGCTGGG 1785

376 AGCACAUC A UGCAAGCA 84 TGCTTGCA GGCTAGCTACAACGA GATGTGCT 1786

378 CACAUCAU G CAAGCAGG 85 CCTGCTTG GGCTAGCTACAACGA ATGATGTG 1787

382 UCAUGCAA G CAGGCCAG 86 CTGGCCTG GGCTAGCTACAACGA TTGCATGA 1788

386 GCAAGCAG G CCAGACAC 87 GTGTCTGG GGCTAGCTACAACGA CTGCTTGC 1789

391 CAGGCCAG A CACUGCAU 88 ATGCAGTG GGCTAGCTACAACGA CTGGCCTG 1790

393 GGCCAGAC A CUGCAUCU 89 AGATGCAG GGCTAGCTACAACGA GTCTGGCC 1791

396 CAGACACU G CAUCUCCA 90 TGGAGATG GGCTAGCTACAACGA AGTGTCTG 1792

398 GACACUGC A UCUCCAAU 91 ATTGGAGA GGCTAGCTACAACGA GCAGTGTC 1793

405 CAUCUCCA A UGCAGGGG 92 CCCCTGCA GGCTAGCTACAACGA TGGAGATG 1794

407 UCUCCAAU G CAGGGGGG 93 CCCCCCTG GGCTAGCTACAACGA ATTGGAGA 1795

418 GGGGGGAA G CAGCCCAU 94 ATGGGCTG GGCTAGCTACAACGA TTCCCCCC 1796

421 GGGAAGCA G CCCAUAAA 95 TTTATGGG GGCTAGCTACAACGA TGCTTCCC 1797

425 AGCAGCCC A UAAAUGGU 96 ACCATTTA GGCTAGCTACAACGA GGGCTGCT 1798

429 GCCCAUAA A UGGUCUUU 97 AAAGACCA GGCTAGCTACAACGA TTATGGGC 1799

432 CAUAAAUG G UCUUUGCC 98 GGCAAAGA GGCTAGCTACAACGA CATTTATG 1800

438 UGGUCUUU G CCUGAAAU 99 ATTTCAGG GGCTAGCTACAACGA AAAGACCA 1801

445 UGCCUGAA A UGGUGAGU 100 ACTCACCA GGCTAGCTACAACGA TTCAGGCA 1802 448 CUGAAAUG G UGAGUAAG 101 CTTACTCA GGCTAGCTACAACGA CATTTCAG 1803

452 AAUGGUGA G UAAGGAAA 102 TTTCCTTA GGCTAGCTACAACGA TCACCATT 1804

461 UAAGGAAA G CGAAAGGC 103 GCCTTTCG GGCTAGCTACAACGA TTTCCTTA 1805

468 AGCGAAAG G CUGAGCAU 104 ATGCTCAG GGCTAGCTACAACGA CTTTCGCT 1806

473 AAGGCUGA G CAUAACUA 105 TAGTTATG GGCTAGCTACAACGA TCAGCCTT 1807

475 GGCUGAGC A UAACUAAA 106 TTTAGTTA GGCTAGCTACAACGA GCTCAGCC 1808

478 UGAGCAUA A CUAAAUCU 107 AGATTTAG GGCTAGCTACAACGA TATGCTCA 1809

483 AUAACUAA A UCUGCCUG 108 CAGGCAGA GGCTAGCTACAACGA TTAGTTAT 1810

487 CUAAAUCU G CCUGUGGA 109 TCCACAGG GGCTAGCTACAACGA AGATTTAG 1811

491 AUCUGCCU G UGGAAGAA 110 TTCTTCCA GGCTAGCTACAACGA AGGCAGAT 1812

500 UGGAAGAA A UGGCAAAC 111 GTTTGCCA GGCTAGCTACAACGA TTCTTCCA 1813

503 AAGAAAUG G CAAACAAU 112 ATTGTTTG GGCTAGCTACAACGA CATTTCTT 1814

507 AAUGGCAA A CAAUUCUG 113 CAGAATTG GGCTAGCTACAACGA TTGCCATT 1815

510 GGCAAACA A UUCUGCAG 114 CTGCAGAA GGCTAGCTACAACGA TGTTTGCC 1816

515 ACAAUUCU G CAGUACUU 115 AAGTACTG GGCTAGCTACAACGA AGAATTGT 1817

518 AUUCUGCA G UACUUUAA 116 TTAAAGTA GGCTAGCTACAACGA TGCAGAAT 1818

520 UCUGCAGU A CUUUAACC 117 GGTTAAAG GGCTAGCTACAACGA ACTGCAGA 1819

526 GUACUUUA A CCUUGAAC 118 GTTCAAGG GGCTAGCTACAACGA TAAAGTAC 1820

533 AACCUUGA A CACAGCUC 119 GAGCTGTG GGCTAGCTACAACGA TCAAGGTT 1821

535 CCUUGAAC A CAGCUCAA 120 TTGAGCTG GGCTAGCTACAACGA GTTCAAGG 1822

538 UGAACACA G CUCAAGCA 121 TGCTTGAG GGCTAGCTACAACGA TGTGTTCA 1823

544 CAGCUCAA G CAAACCAC 122 GTGGTTTG GGCTAGCTACAACGA TTGAGCTG 1824

548 UCAAGCAA A CCACACUG 123 CAGTGTGG GGCTAGCTACAACGA TTGCTTGA 1825

551 AGCAAACC A CACUGGCU 124 AGCCAGTG GGCTAGCTACAACGA GGTTTGCT 1826

553 CAAACCAC A CUGGCUUC 125 GAAGCCAG GGCTAGCTACAACGA GTGGTTTG 1827

557 CCACACUG G CUUCUACA 126 TGTAGAAG GGCTAGCTACAACGA CAGTGTGG 1828

563 UGGCUUCU A CAGCUGCA 127 TGCAGCTG GGCTAGCTACAACGA AGAAGCCA 1829

566 CUUCUACA G CUGCAAAU 128 ATTTGCAG GGCTAGCTACAACGA TGTAGAAG 1830

569 CUACAGCU G CAAAUAUC 129 GATATTTG GGCTAGCTACAACGA AGCTGTAG 1831

573 AGCUGCAA A UAUCUAGC 130 GCTAGATA GGCTAGCTACAACGA TTGCAGCT 1832

575 CUGCAAAU A UCUAGCUG 131 CAGCTAGA GGCTAGCTACAACGA ATTTGCAG 1833

580 AAUAUCUA G CUGUACCU 132 AGGTACAG GGCTAGCTACAACGA TAGATATT 1834

583 AUCUAGCU G UACCUACU 133 AGTAGGTA GGCTAGCTACAACGA AGCTAGAT 1835

585 CUAGCUGU A CCUACUUC 134 GAAGTAGG GGCTAGCTACAACGA ACAGCTAG 1836

589 CUGUACCU A CUUCAAAG 135 CTTTGAAG GGCTAGCTACAACGA AGGTACAG 1837

607 AGAAGGAA A CAGAAUCU 136 AGATTCTG GGCTAGCTACAACGA TTCCTTCT 1838

612 GAAACAGA A UCUGCAAU 137 ATTGGAGA GGCTAGCTACAACGA TCTGTTTC 1839

616 CAGAAUCU G CAAUCUAU 138 ATAGATTG GGCTAGCTACAACGA AGATTCTG 1840

619 AAUCUGCA A UCUAUAUA 139 TATATAGA GGCTAGCTACAACGA TGCAGATT 1841

623 UGCAAUCU A UAUAUUUA 140 TAAATATA GGCTAGCTACAACGA AGATTGCA 1842

625 CAAUCUAU A UAUUUAUU 141 AATAAATA GGCTAGCTACAACGA ATAGATTG 1843

627 AUCUAUAU A UUUAUUAG 142 CTAATAAA GGCTAGCTACAACGA ATATAGAT 1844

631 AUAUAUUU A UUAGUGAU 143 ATCACTAA GGCTAGCTACAACGA AAATATAT 1845

635 AUUUAUUA G UGAUACAG 144 CTGTATCA GGCTAGCTACAACGA TAATAAAT 1846

638 UAUUAGUG A UACAGGUA 145 TACCTGTA GGCTAGCTACAACGA CACTAATA 1847

640 UUAGUGAU A CAGGUAGA 146 TCTACCTG GGCTAGCTACAACGA ATCACTAA 1848

644 UGAUACAG G UAGACCUU 147 AAGGTCTA GGCTAGCTACAACGA CTGTATCA 1849

648 ACAGGUAG A CCUUUCGU 148 ACGAAAGG GGCTAGCTACAACGA CTACCTGT 1850

655 GACCUUUC G UAGAGAUG 149 CATCTCTA GGCTAGCTACAACGA GAAAGGTC 1851

661 UCGUAGAG A UGUACAGU 150 ACTGTACA GGCTAGCTACAACGA CTCTACGA 1852

663 GUAGAGAU G UACAGUGA 151 TCACTGTA GGCTAGCTACAACGA ATCTCTAC 1853

665 AGAGAUGU A CAGUGAAA 152 TTTCACTG GGCTAGCTACAACGA ACATCTCT 1854

894 GGGCAUUU G UAUAAGAC 205 GTCTTATA GGCTAGCTACAACGA AAATGCCC 1907

896 GCAUUUGU A UAAGACAA 206 TTGTCTTA GGCTAGCTACAACGA ACAAATGC 1908

901 UGUAUAAG A CAAACUAU 207 ATAGTTTG GGCTAGCTACAACGA CTTATACA 1909

905 UAAGACAA A CUAUCUCA 208 TGAGATAG GGCTAGCTACAACGA TTGTCTTA 1910

908 GACAAACU A UCUCACAC 209 GTGTGAGA GGCTAGCTACAACGA AGTTTGTC 1911

913 ACUAUCUC A CACAUCGA 210 TCGATGTG GGCTAGCTACAACGA GAGATAGT 1912

915 UAUCUCAC A CAUCGACA 211 TGTCGATG GGCTAGCTACAACGA GTGAGATA 1913

917 UCUCACAC A UCGACAAA 212 TTTGTCGA GGCTAGCTACAACGA GTGTGAGA 1914

921 ACACAUCG A CAAACCAA 213 TTGGTTTG GGCTAGCTACAACGA CGATGTGT 1915

925 AUCGACAA A CCAAUACA 214 TGTATTGG GGCTAGCTACAACGA TTGTCGAT 1916

929 ACAAACCA A UACAAUCA 215 TGATTGTA GGCTAGCTACAACGA TGGTTTGT 1917

931 AAACCAAU A CAAUCAUA 216 TATGATTG GGCTAGCTACAACGA ATTGGTTT 1918

934 CCAAUACA A UCAUAGAU 217 ATCTATGA GGCTAGCTACAACGA TGTATTGG 1919

937 AUACAAUC A UAGAUGUC 218 GACATCTA GGCTAGCTACAACGA GATTGTAT 1920

941 AAUCAUAG A UGUCCAAA 219 TTTGGACA GGCTAGCTACAACGA CTATGATT 1921

943 UCAUAGAU G UCCAAAUA 220 TATTTGGA GGCTAGCTACAACGA ATCTATGA 1922

949 AUGUCCAA A UAAGCACA 221 TGTGCTTA GGCTAGCTACAACGA TTGGACAT 1923

953 CCAAAUAA G CACACCAC 222 GTGGTGTG GGCTAGCTACAACGA TTATTTGG 1924

955 AAAUAAGC A CACCACGC 223 GCGTGGTG GGCTAGCTACAACGA GCTTATTT 1925

957 AUAAGCAC A CCACGCCC 224 GGGCGTGG GGCTAGCTACAACGA GTGCTTAT 1926

960 AGCACACC A CGCCCAGU 225 ACTGGGCG GGCTAGCTACAACGA GGTGTGCT 1927

962 CACACCAC G CCCAGUCA 226 TGACTGGG GGCTAGCTACAACGA GTGGTGTG 1928

967 CACGCCCA σ UCAAAUUA 227 TAATTTGA GGCTAGCTACAACGA TGGGCGTG 1929

972 CCAGUCAA A UUACUUAG 228 CTAAGTAA GGCTAGCTACAACGA TTGACTGG 1930

975 GUCAAAUU A CUUAGAGG 229 CCTCTAAG GGCTAGCTACAACGA AATTTGAC 1931

983 ACUUAGAG G CCAUACUC 230 GAGTATGG GGCTAGCTACAACGA CTCTAAGT 1932

986 UAGAGGCC A UACUCUUG 231 CAAGAGTA GGCTAGCTACAACGA GGCCTCTA 1933

988 GAGGCCAU A CUCUUGUC 232 GACAAGAG GGCTAGCTACAACGA ATGGCCTC 1934

994 AUACUCUU G UCCUCAAU 233 ATTGAGGA GGCTAGCTACAACGA AAGAGTAT 1935

1001 UGUCCUCA A UUGUACUG 234 CAGTACAA GGCTAGCTACAACGA TGAGGACA 1936

1004 CCUCAAUU G UACUGCUA 235 TAGCAGTA GGCTAGCTACAACGA AATTGAGG 1937

1006 UCAAUUGU A CUGCUACC 236 GGTAGCAG GGCTAGCTACAACGA ACAATTGA 1938

1009 AUUGUACU G CUACCACU 237 AGTGGTAG GGCTAGCTACAACGA AGTACAAT 1939

1012 GUACUGCU A CCACUCCC 238 GGGAGTGG GGCTAGCTACAACGA AGCAGTAC 1940

1015 CUGCUACC A CUCCCUUG 239 CAAGGGAG GGCTAGCTACAACGA GGTAGCAG 1941

1025 UCCCUUGA A CACGAGAG 240 CTCTCGTG GGCTAGCTACAACGA TCAAGGGA 1942

1027 CCUUGAAC A CGAGAGUU 241 AACTCTCG GGCTAGCTACAACGA GTTCAAGG 1943

1033 ACACGAGA G UUCAAAUG 242 CATTTGAA GGCTAGCTACAACGA TCTCGTGT 1944

1039 GAGUUCAA A UGACCUGG 243 CCAGGTCA GGCTAGCTACAACGA TTGAACTC 1945

1042 UUCAAAUG A CCUGGAGU 244 ACTCCAGG GGCTAGCTACAACGA CATTTGAA 1946

1049 GACCUGGA G UUACCCUG 245 CAGGGTAA GGCTAGCTACAACGA TCCAGGTC 1947

1052 CUGGAGUU A CCCUGAUG 246 CATCAGGG GGCTAGCTACAACGA AACTCCAG 1948

1058 UUACCCUG A UGAAAAAA 247 TTTTTTCA GGCTAGCTACAACGA CAGGGTAA 1949

1067 UGAAAAAA A UAAGAGAG 248 CTCTCTTA GGCTAGCTACAACGA TTTTTTCA 1950

1075 AUAAGAGA G CUUCCGUA 249 TACGGAAG GGCTAGCTACAACGA TCTCTTAT 1951

1081 GAGCUUCC G UAAGGCGA 250 TCGCCTTA GGCTAGCTACAACGA GGAAGCTC 1952

1086 UCCGUAAG G CGACGAAU 251 ATTCGTCG GGCTAGCTACAACGA CTTACGGA 1953

1089 GUAAGGCG A CGAAUUGA 252 TCAATTCG GGCTAGCTACAACGA CGCCTTAC 1954

1093 GGCGACGA A UUGACCAA 253 TTGGTCAA GGCTAGCTACAACGA TCGTCGCC 1955

1097 ACGAAUUG A CCAAAGCA 254 TGCTTTGG GGCTAGCTACAACGA CAATTCGT 1956

1103 UGACCAAA G CAAUUCCC 255 GGGAATTG GGCTAGCTACAACGA TTTGGTCA 1957

1106 CCAAAGCA A UUCCCAUG 256 CATGGGAA GGCTAGCTACAACGA TGCTTTGG 1958 1112 CAAUUCCC A UGCCAACA 257 TGTTGGCA GGCTAGCTACAACGA GGGAATTG 1959

1114 AUUCCCAU G CCAACAUA 258 TATGTTGG GGCTAGCTACAACGA ATGGGAAT 1960

1118 CCAUGCCA A CAUAUUCU 259 AGAATATG GGCTAGCTACAACGA TGGCATGG 1961

1120 AUGCCAAC A UAUUCUAC 260 GTAGAATA GGCTAGCTACAACGA GTTGGCAT 1962

1122 GCCAACAU A UUCUACAG 261 CTGTAGAA GGCTAGCTACAACGA ATGTTGGC 1963

1127 CAUAUUCU A CAGUGUUC 262 GAACACTG GGCTAGCTACAACGA AGAATATG 1964

1130 AUUCUACA G UGUUCUUA 263 TAAGAACA GGCTAGCTACAACGA TGTAGAAT 1965

1132 UCUACAGU G UUCUUACU 264 AGTAAGAA GGCTAGCTACAACGA ACTGTAGA 1966

1138 GUGUUCUU A CUAUUGAC 265 GTCAATAG GGCTAGCTACAACGA AAGAACAC 1967

1141 UUCUUACU A UUGACAAA 266 TTTGTCAA GGCTAGCTACAACGA AGTAAGAA 1968

1145 UACUAUUG A CAAAAUGC 267 GCATTTTG GGCTAGCTACAACGA CAATAGTA 1969

1150 UUGACAAA A UGCAGAAC 268 GTTCTGCA GGCTAGCTACAACGA TTTGTCAA 1970

1152 GACAAAAU G CAGAACAA 269 TTGTTCTG GGCTAGCTACAACGA ATTTTGTC 1971

1157 AAUGCAGA A CAAAGACA 270 TGTCTTTG GGCTAGCTACAACGA TCTGCATT 1972

1163 GAACAAAG A CAAAGGAC 271 GTCCTTTG GGCTAGCTACAACGA CTTTGTTC 1973

1170 GACAAAGG A CUUUAUAC 272 GTATAAAG GGCTAGCTACAACGA CCTTTGTC 1974

1175 AGGACUUU A UACUUGUC 273 GACAAGTA GGCTAGCTACAACGA AAAGTCCT 1975

1177 GACUUUAU A CUUGUCGU 274 ACGACAAG GGCTAGCTACAACGA ATAAAGTC 1976

1181 UUAUACUU G UCGUGUAA 275 TTACACGA GGCTAGCTACAACGA AAGTATAA 1977

1184 UACUUGUC G UGUAAGGA 276 TCCTTACA GGCTAGCTACAACGA GACAAGTA 1978

1186 CUUGUCGU G UAAGGAGU 277 ACTCCTTA GGCTAGCTACAACGA ACGACAAG 1979

1193 UGUAAGGA G UGGACCAU 278 ATGGTCCA GGCTAGCTACAACGA TCCTTACA 1980

1197 AGGAGUGG A CCAUCAUU 279 AATGATGG GGCTAGCTACAACGA CCACTCCT 1981

1200 AGUGGACC A UCAUUCAA 280 TTGAATGA GGCTAGCTACAACGA GGTCCACT 1982

1203 GGACCAUC A UUCAAAUG 281 GATTTGAA GGCTAGCTACAACGA GATGGTCC 1983

1209 UCAUUCAA A UCUGUUAA 282 TTAACAGA GGCTAGCTACAACGA TTGAATGA 1984

1213 UCAAAUCU G UUAACACC 283 GGTGTTAA GGCTAGCTACAACGA AGATTTGA 1985

1217 AUCUGUUA A CACCUCAG 284 CTGAGGTG GGCTAGCTACAACGA TAACAGAT 1986

1219 CUGUUAAC A CCUCAGUG 285 CACTGAGG GGCTAGCTACAACGA GTTAACAG 1987

1225 ACACOJCA G UGCAUAUA 286 TATATGCA GGCTAGCTACAACGA TGAGGTGT 1988

1227 ACCUCAGU G CAUAUAUA 287 TATATATG GGCTAGCTACAACGA ACTGAGGT 1989

1229 CUCAGUGC A UAUAUAUG 288 CATATATA GGCTAGCTACAACGA GCACTGAG 1990

1231 CAGUGCAU A UAUAUGAU 289 ATCATATA GGCTAGCTACAACGA ATGCACTG 1991

1233 GUGCAUAU A UAUGAUAA 290 TTATCATA GGCTAGCTACAACGA ATATGCAC 1992

1235 GCAUAUAU A UGAUAAAG 291 CTTTATCA GGCTAGCTACAACGA ATATATGC 1993

1238 UAUAUAUG A UAAAGCAU 292 ATGCTTTA GGCTAGCTACAACGA CATATATA 1994

1243 AUGAUAAA G CAUUCAUC 293 GATGAATG GGCTAGCTACAACGA TTTATCAT 1995

1245 GAUAAAGC A UUCAUCAC 294 GTGATGAA GGCTAGCTACAACGA GCTTTATC 1996

1249 AAGCAUUC A UCACUGUG 295 CACAGTGA GGCTAGCTACAACGA GAATGCTT 1997

1252 CAUUCAUC A CUGUGAAA 296 TTTCACAG GGCTAGCTACAACGA GATGAATG 1998

1255 UCAUCACU G UGAAACAU 297 ATGTTTCA GGCTAGCTACAACGA AGTGATGA 1999

1260 ACUGUGAA A CAUCGAAA 298 TTTCGATG GGCTAGCTACAACGA TTCACAGT 2000

1262 UGUGAAAC A UCGAAAAC 299 GTTTTCGA GGCTAGCTACAACGA GTTTCACA 2001

1269 CAUCGAAA A CAGCAGGU 300 ACCTGCTG GGCTAGCTACAACGA TTTCGATG 2002

1272 CGAAAACA G CAGGUGCU 301 AGCACCTG GGCTAGCTACAACGA TGTTTTCG 2003

1276 AACAGCAG G UGCUUGAA 302 TTCAAGCA GGCTAGCTACAACGA CTGCTGTT 2004

1278 CAGCAGGU G CUUGAAAC 303 GTTTCAAG GGCTAGCTACAACGA ACCTGCTG 2005

1285 UGCUUGAA A CCGUAGCU 304 AGCTACGG GGCTAGCTACAACGA TTCAAGCA 2006

1288 UUGAAACC G UAGCUGGC 305 GCCAGCTA GGCTAGCTACAACGA GGTTTCAA 2007

1291 AAACCGUA G CUGGCAAG 306 CTTGCCAG GGCTAGCTACAACGA TACGGTTT 2008

1295 CGUAGCUG G CAAGCGGU 307 ACCGCTTG GGCTAGCTACAACGA CAGCTACG 2009

1299 GCUGGCAA G CGGUCUUA 308 TAAGACCG GGCTAGCTACAACGA TTGCCAGC 2010 1302 GGCAAGCG G UCUUACCG 309 CGGTAAGA GGCTAGCTACAACGA CGCTTGCC 2011

1307 GCGGUCUU A CCGGCUCU 310 AGAGCCGG GGCTAGCTACAACGA AAGACCGC 2012

1311 UCUUACCG G CUCUCUAU 311 ATAGAGAG GGCTAGCTACAACGA CGGTAAGA 2013

1318 GGCUCUCU A UGAAAGUG 312 CACTTTCA GGCTAGCTACAACGA AGAGAGCC 2014

1324 CUAUGAAA G UGAAGGCA 313 TGCCTTCA GGCTAGCTACAACGA TTTCATAG 2015

1330 AAGUGAAG G CAUUUCCC 314 GGGAAATG GGCTAGCTACAACGA CTTCACTT 2016

1332 GUGAAGGC A UUUCCCUC 315 GAGGGAAA GGCTAGCTACAACGA GCCTTCAC 2017

1341 UUUCCCUC G CCGGAAGU 316 ACTTCCGG GGCTAGCTACAACGA GAGGGAAA 2018

1348 CGCCGGAA G UUGUAUGG 317 CCATACAA GGCTAGCTACAACGA TTCCGGCG 2019

1351 CGGAAGUU G UAUGGUUA 318 TAACCATA GGCTAGCTACAACGA AACTTCCG 2020

1353 GAAGUUGU A UGGUUAAA 319 TTTAACCA GGCTAGCTACAACGA ACAACTTC 2021

1356 GUUGUAUG G UUAAAAGA 320 TCTTTTAA GGCTAGCTACAACGA CATACAAC 2022

1364 GUUAAAAG A UGGGUUAC 321 GTAACCCA GGCTAGCTACAACGA CTTTTAAC 2023

1368 AAAGAUGG G UUACCUGC 322 GCAGGTAA GGCTAGCTACAACGA CCATCTTT 2024

1371 GAUGGGUU A CCUGCGAC 323 GTCGCAGG GGCTAGCTACAACGA AACCCATC 2025

1375 GGUUACCU G CGACUGAG 324 CTCAGTCG GGCTAGCTACAACGA AGGTAACC 2026

1378 UACCUGCG A CUGAGAAA 325 TTTCTCAG GGCTAGCTACAACGA CGCAGGTA 2027

1386 ACUGAGAA A UCUGCUCG 326 CGAGCAGA GGCTAGCTACAACGA TTCTCAGT 2028

1390 AGAAAUCU G CUCGCUAU 327 ATAGCGAG GGCTAGCTACAACGA AGATTTCT 2029

1394 AUCUGCUC G CUAUUUGA 328 TCAAATAG GGCTAGCTACAACGA GAGCAGAT 2030

1397 UGCUCGCU A UUUGACUC 329 GAGTCAAA GGCTAGCTACAACGA AGCGAGCA 2031

1402 GCUAUUUG A CUCGUGGC 330 GCCACGAG GGCTAGCTACAACGA CAAATAGC 2032

1406 UUUGACUC G UGGCUACU 331 AGTAGCCA GGCTAGCTACAACGA GAGTCAAA 2033

1409 GACUCGUG G CUACUCGU 332 ACGAGTAG GGCTAGCTACAACGA CACGAGTC 2034

1412 UCGUGGCU A CUCGUUAA 333 TTAACGAG GGCTAGCTACAACGA AGCCACGA 2035

1416 GGCUACUC G UUAAUUAU 334 ATAATTAA GGCTAGCTACAACGA GAGTAGCC 2036

1420 ACUCGUUA A UUAUCAAG 335 CTTGATAA GGCTAGCTACAACGA TAACGAGT 2037

1423 CGUUAAUU A UCAAGGAC 336 GTCCTTGA GGCTAGCTACAACGA AATTAACG 2038

1430 UAUCAAGG A CGUAACUG 337 CAGTTACG GGCTAGCTACAACGA CCTTGATA 2039

1432 UCAAGGAC G UAACUGAA 338 TTCAGTTA GGCTAGCTACAACGA GTCCTTGA 2040

1435 AGGACGUA A CUGAAGAG 339 CTCTTCAG GGCTAGCTACAACGA TACGTCCT 2041

1445 UGAAGAGG A UGCAGGGA 340 TCCCTGCA GGCTAGCTACAACGA CCTCTTCA 2042

1447 AAGAGGAU G CAGGGAAU 341 ATTCCCTG GGCTAGCTACAACGA ATCCTCTT 2043

1454 UGCAGGGA A UUAUACAA 342 TTGTATAA GGCTAGCTACAACGA TCCCTGCA 2044

1457 AGGGAAUU A UACAAUCU 343 AGATTGTA GGCTAGCTACAACGA AATTCCCT 2045

1459 GGAAUUAU A CAAUCUUG 344 CAAGATTG GGCTAGCTACAACGA ATAATTCC 2046

1462 AUUAUACA A UCUUGCUG 345 CAGCAAGA GGCTAGCTACAACGA TGTATAAT 2047

1467 ACAAUCUU G CUGAGCAU 346 ATGCTCAG GGCTAGCTACAACGA AAGATTGT 2048

1472 CUUGCUGA G CAUAAAAC 347 GTTTTATG GGCTAGCTACAACGA TCAGCAAG 2049

1474 UGCUGAGC A UAAAACAG 348 CTGTTTTA GGCTAGCTACAACGA GCTCAGCA 2050

1479 AGCAUAAA A CAGUCAAA 349 TTTGACTG GGCTAGCTACAACGA TTTATGCT 2051

1482 AUAAAACA G UCAAAUGU 350 ACATTTGA GGCTAGCTACAACGA TGTTTTAT 2052

1487 ACAGUCAA A UGUGUUUA 351 TAAACACA GGCTAGCTACAACGA TTGACTGT 2053

1489 AGUCAAAU G UGUUUAAA 352 TTTAAACA GGCTAGCTACAACGA ATTTGACT 2054

1491 UCAAAUGU G UUUAAAAA 353 TTTTTAAA GGCTAGCTACAACGA ACATTTGA 2055

1499 GUUUAAAA A CCUCACUG 354 CAGTGAGG GGCTAGCTACAACGA TTTTAAAC 2056

1504 AAAACCUC A CUGCCACU 355 AGTGGCAG GGCTAGCTACAACGA GAGGTTTT 2057

1507 ACCUCACU G CCACUCUA 356 TAGAGTGG GGCTAGCTACAACGA AGTGAGGT 2058

1510 UCACUGCC A CUCUAAUU 357 AATTAGAG GGCTAGCTACAACGA GGCAGTGA 2059

1516 CCACUCUA A UUGUCAAU 358 ATTGACAA GGCTAGCTACAACGA TAGAGTGG 2060

1519 CUCUAAUU G UCAAUGUG 359 CACATTGA GGCTAGCTACAACGA AATTAGAG 2061

1523 AAUUGUCA A UGUGAAAC 360 GTTTCACA GGCTAGCTACAACGA TGACAATT 2062 1525 UUGUCAAU G UGAAACCC 361 GGGTTTCA GGCTAGCTACAACGA ATTGACAA 2063

1530 AAUGUGAA A CCCCAGAU 362 ATCTGGGG GGCTAGCTACAACGA TTCACATT 2064

1537 AACCCCAG A UUUACGAA 363 TTCGTAAA GGCTAGCTACAACGA CTGGGGTT 2065

1541 CCAGAUUU A CGAAAAGG 364 CCTTTTCG GGCTAGCTACAACGA AAATCTGG 2066

1549 ACGAAAAG G CCGUGUCA 365 TGACACGG GGCTAGCTACAACGA CTTTTCGT 2067

1552 AAAAGGCC G UGUCAUCG 366 CGATGACA GGCTAGCTACAACGA GGCCTTTT 2068

1554 AAGGCCGU G UCAUCGUU 367 AACGATGA GGCTAGCTACAACGA ACGGCCTT 2069

1557 GCCGUGUC A UCGUUUCC 368 GGAAACGA GGCTAGCTACAACGA GACACGGC 2070

1560 GUGUCAUC G UUUCCAGA 369 TCTGGAAA GGCTAGCTACAACGA GATGACAC 2071

1568 GUUUCCAG A CCCGGCUC 370 GAGCCGGG GGCTAGCTACAACGA CTGGAAAC 2072

1573 CAGACCCG G CUCUCUAC 371 GTAGAGAG GGCTAGCTACAACGA CGGGTCTG 2073

1580 GGCUCUCU A CCCACUGG 372 CCAGTGGG GGCTAGCTACAACGA AGAGAGCC 2074

1584 CUCUACCC A CUGGGCAG 373 CTGCCCAG GGCTAGCTACAACGA GGGTAGAG 2075

1589 CCCACUGG G CAGCAGAC 374 GTCTGCTG GGCTAGCTACAACGA CCAGTGGG 2076

1592 ACUGGGCA G CAGACAAA 375 TTTGTCTG GGCTAGCTACAACGA TGCCCAGT 2077

1596 GGCAGCAG A CAAAUCCU 376 AGGATTTG GGCTAGCTACAACGA CTGCTGCC 2078

1600 GCAGACAA A UCCUGACU 377 AGTCAGGA GGCTAGCTACAACGA TTGTCTGC 2079

1606 AAAUCCUG A CUUGUACC 378 GGTACAAG GGCTAGCTACAACGA CAGGATTT 2080

1610 CCUGACUU G UACCGCAU 379 ATGCGGTA GGCTAGCTACAACGA AAGTCAGG 2081

1612 UGACUUGU A CCGCAUAU 380 ATATGCGG GGCTAGCTACAACGA ACAAGTCA 2082

1615 CUUGUACC G CAUAUGGU 381 ACCATATG GGCTAGCTACAACGA GGTACAAG 2083

1617 UGUACCGC A UAUGGUAU 382 ATACCATA GGCTAGCTACAACGA GCGGTACA 2084

1619 UACCGCAU A UGGUAUCC 383 GGATACCA GGCTAGCTACAACGA ATGCGGTA 2085

1622 CGCAUAUG G UAUCCCUC 384 GAGGGATA GGCTAGCTACAACGA CATATGCG 2086

1624 CAUAUGGU A UCCCUCAA 385 TTGAGGGA GGCTAGCTACAACGA ACCATATG 2087

1632 AUCCCUCA A CCUACAAU 386 ATTGTAGG GGCTAGCTACAACGA TGAGGGAT 2088

1636 CUCAACCU A CAAUCAAG 387 CTTGATTG GGCTAGCTACAACGA AGGTTGAG 2089

1639 AACCUACA A UCAAGUGG 388 CCACTTGA GGCTAGCTACAACGA TGTAGGTT 2090

1644 ACAAUCAA G UGGUUCUG 389 CAGAACCA GGCTAGCTACAACGA TTGATTGT 2091

1647 AUCAAGUG G UUCUGGCA 390 TGCCAGAA GGCTAGCTACAACGA CACTTGAT 2092

1653 UGGUUCUG G CACCCCUG 391 CAGGGGTG GGCTAGCTACAACGA CAGAACCA 2093

1655 GUUCUGGC A CCCCUGUA 392 TACAGGGG GGCTAGCTACAACGA GCCAGAAC 2094

1661 GCACCCCU G UAACCAUA 393 TATGGTTA GGCTAGCTACAACGA AGGGGTGC 2095

1664 CCCCUGUA A CCAUAAUC 394 GATTATGG GGCTAGCTACAACGA TACAGGGG 2096

1667 CUGUAACC A UAAUCAUU 395 AATGATTA GGCTAGCTACAACGA GGTTACAG 2097

1670 UAACCAUA A UCAUUCCG 396 CGGAATGA GGCTAGCTACAACGA TATGGTTA 2098

1673 CCAUAAUC A UUCCGAAG 397 CTTCGGAA GGCTAGCTACAACGA GATTATGG 2099

1681 AUUCCGAA G CAAGGUGU 398 ACACCTTG GGCTAGCTACAACGA TTCGGAAT 2100

1686 GAAGCAAG G UGUGACUU 399 AAGTCACA GGCTAGCTACAACGA CTTGCTTC 2101

1688 AGCAAGGU G UGACUUUU 400 AAAAGTCA GGCTAGCTACAACGA ACCTTGCT 2102

1691 AAGGUGUG A CUUUUGUU 401 AACAAAAG GGCTAGCTACAACGA CACACCTT 2103

1697 UGACUUUU G UUCCAAUA 402 TATTGGAA GGCTAGCTACAACGA AAAAGTCA 2104

1703 UUGUUCCA A UAAUGAAG 403 CTTCATTA GGCTAGCTACAACGA TGGAACAA 2105

1706 UUCCAAUA A UGAAGAGU 404 ACTCTTCA GGCTAGCTACAACGA TATTGGAA 2106

1713 AAUGAAGA G UCCUUUAU 405 ATAAAGGA GGCTAGCTACAACGA TCTTCATT 2107

1720 AGUCCUUU A UCCUGGAU 406 ATCCAGGA GGCTAGCTACAACGA AAAGGACT 2108

1727 UAUCCUGG A UGCUGACA 407 TGTCAGCA GGCTAGCTACAACGA CCAGGATA 2109

1729 UCCUGGAU G CUGACAGC 408 GCTGTCAG GGCTAGCTACAACGA ATCCAGGA 2110

1733 GGAUGCUG A CAGCAACA 409 TGTTGCTG GGCTAGCTACAACGA CAGCATCC 2111

1736 UGCUGACA G CAACAUGG 410 CCATGTTG GGCTAGCTACAACGA TGTCAGCA 2112

1739 UGACAGCA A CAUGGGAA 411 TTCCCATG GGCTAGCTACAACGA TGCTGTCA 2113

1741 ACAGCAAC A UGGGAAAC 412 GTTTCCCA GGCTAGCTACAACGA GTTGCTGT 2114 1748 CAUGGGAA A CAGAAUUG 413 CAATTCTG GGCTAGCTACAACGA TTCCCATG 2115

1753 GAAACAGA A UUGAGAGC 414 GCTCTCAA GGCTAGCTACAACGA TCTGTTTC 2116

1760 AAUUGAGA G CAUCACUC 415 GAGTGATG GGCTAGCTACAACGA TCTCAATT 2117

1762 UUGAGAGC A UCACUCAG 416 CTGAGTGA GGCTAGCTACAACGA GCTCTCAA 2118

1765 AGAGCAUC A CUCAGCGC 417 GCGCTGAG GGCTAGCTACAACGA GATGCTCT 2119

1770 AUCACUCA G CGCAUGGC 418 GCCATGCG GGCTAGCTACAACGA TGAGTGAT 2120

1772 CACUCAGC G CAUGGGAA 419 TTGCCATG GGCTAGCTACAACGA GCTGAGTG 2121

1774 CUCAGGGC A UGGCAAUA 420 TATTGCCA GGCTAGCTACAACGA GCGCTGAG 2122

1777 AGCGCAUG G CAAUAAUA 421 TATTATTG GGCTAGCTACAACGA CATGCGCT 2123

1780 GCAUGGCA A UAAUAGAA 422 TTCTATTA GGCTAGCTACAACGA TGCCATGC 2124

1783 UGGCAAUA A UAGAAGGA 423 TCCTTCTA GGCTAGCTACAACGA TATTGCCA 2125

1796 AGGAAAGA A UAAGAUGG 424 CCATCTTA GGCTAGCTACAACGA TCTTTCCT 2126

1801 AGAAUAAG A UGGCUAGC 425 GCTAGCCA GGCTAGCTACAACGA CTTATTCT 2127

1804 AUAAGAUG G CUAGCACC 426 GGTGCTAG GGCTAGCTACAACGA CATCTTAT 2128

1808 GAUGGCUA G CACCUUGG 427 CCAAGGTG GGCTAGCTACAACGA TAGCCATC 2129

1810 UGGCUAGC A CCUUGGUU 428 AACCAAGG GGCTAGCTACAACGA GCTAGCCA 2130

1816 GCACCUUG G UUGUGGCU 429 AGCCACAA GGCTAGCTACAACGA CAAGGTGC 2131

1819 CCUUGGUU G UGGCUGAC 430 GTCAGCCA GGCTAGCTACAACGA AACCAAGG 2132

1822 UGGUUGUG G CUGACUCU 431 AGAGTCAG GGCTAGCTACAACGA CAGAACCA 2133

1826 UGUGGCUG A CUCUAGAA 432 TTCTAGAG GGCTAGCTACAACGA CAGCCACA 2134

1834 ACUCUAGA A UUUCUGGA 433 TCCAGAAA GGCTAGCTACAACGA TCTAGAGT 2135

1843 UUUCUGGA A UCUACAUU 434 AATGTAGA GGCTAGCTACAACGA TCCAGAAA 2136

1847 UGGAAUCU A CAUOUGCA 435 TGCAAATG GGCTAGCTACAACGA AGATTCCA 2137

1849 GAAUCUAC A UUUGCAUA 436 TATGCAAA GGCTAGCTACAACGA GTAGATTC 2138

1853 CUACAUUU G CAUAGCUU 437 AAGCTATG GGCTAGCTACAACGA AAATGTAG 2139

1855 ACAUUUGC A UAGCUUCC 438 GGAAGCTA GGCTAGCTACAACGA GCAAATGT 2140

1858 UUUGCAUA G CUUCCAAU 439 ATTGGAAG GGCTAGCTACAACGA TATGCAAA 2141

1865 AGCUUCCA A UAAAGUUG 440 CAACTTTA GGCTAGCTACAACGA TGGAAGCT 2142

1870 CCAAUAAA G UUGGGACU 441 AGTCCCAA GGCTAGCTACAACGA TTTATTGG 2143

1876 AAGUUGGG A CUGUGGGA 442 TCCCACAG GGCTAGCTACAACGA CCCAACTT 2144

1879 UUGGGACU G UGGGAAGA 443 TCTTCCCA GGCTAGCTACAACGA AGTCCCAA 2145

1889 GGGAAGAA A CAUAAGCU 444 AGCTTATG GGCTAGCTACAACGA TTCTTCCC 2146

1891 GAAGAAAC A UAAGCUUU 445 AAAGCTTA GGCTAGCTACAACGA GTTTCTTC 2147

1895 AAACAUAA G CUUUUAUA 446 TATAAAAG GGCTAGCTACAACGA TTATGTTT 2148

1901 AAGCUUUU A UAUCACAG 447 CTGTGATA GGCTAGCTACAACGA AAAAGCTT 2149

1903 GCUUUUAU A UCACAGAU 448 ATCTGTGA GGCTAGCTACAACGA ATAAAAGC 2150

1906 UUUAUAUC A CAGAUGUG 449 CACATCTG GGCTAGCTACAACGA GATATAAA 2151

1910 UAUCACAG A UGUGCCAA 450 TTGGCACA GGCTAGCTACAACGA CTGTGATA 2152

1912 UCACAGAU G UGCCAAAU 451 ATTTGGCA GGCTAGCTACAACGA ATCTGTGA 2153

1914 ACAGAUGU G CCAAAUGG 452 CCATTTGG GGCTAGCTACAACGA ACATCTGT 2154

1919 UGUGCCAA A UGGGUUUC 453 GAAACCCA GGCTAGCTACAACGA TTGGCACA 2155

1923 CCAAAUGG G UUUCAUGU 454 ACATGAAA GGCTAGCTACAACGA CCATTTGG 2156

1928 UGGGUUUC A UGUUAACU 455 AGTTAACA GGCTAGCTACAACGA GAAACCCA 2157

1930 GGUUUCAU G UUAACUUG 456 CAAGTTAA GGCTAGCTACAACGA ATGAAACC 2158

1934 UCAUGUUA A CUUGGAAA 457 TTTCCAAG GGCTAGCTACAACGA TAACATGA 2159

1945 UGGAAAAA A UGCCGACG 458 CGTCGGCA GGCTAGCTACAACGA TTTTTCCA 2160

1947 GAAAAAAU G CCGACGGA 459 TCCGTCGG GGCTAGCTACAACGA ATTTTTTC 2161

1951 AAAUGCCG A CGGAAGGA 460 TCCTTCCG GGCTAGCTACAACGA CGGCATTT 2162

1964 AGGAGAGG A CCUGAAAC 461 GTTTCAGG GGCTAGCTACAACGA CCTCTCCT 2163

1971 GACCUGAA A CUGUCUUG 462 CAAGACAG GGCTAGCTACAACGA TTCAGGTC 2164

1974 CUGAAACU G UCUUGCAC 463 GTGCAAGA GGCTAGCTACAACGA AGTTTCAG 2165

1979 ACUGUCUU G CACAGUUA 464 TAACTGTG GGCTAGCTACAACGA AAGACAGT 2166 1981 UGUCUUGC A CAGUUAAC 465 GTTAACTG GGCTAGCTACAACGA GCAAGACA 2167

1984 CUUGCACA G UUAACAAG 466 CTTGTTAA GGCTAGCTACAACGA TGTGCAAG 2168

1988 CACAGUUA A CAAGUUCU 467 AGAACTTG GGCTAGCTACAACGA TAACTGTG 2169

1992 GUUAACAA G UUCUUAUA 468 TATAAGAA GGCTAGCTACAACGA TTGTTAAC 2170

1998 AAGUUCUU A UACAGAGA 469 TCTCTGTA GGCTAGCTACAACGA AAGAACTT 2171

2000 GUUCUUAU A CAGAGACG 470 CGTCTCTG GGCTAGCTACAACGA ATAAGAAC 2172

2006 AUACAGAG A CGUUACUU 471 AAGTAACG GGCTAGCTACAACGA CTCTGTAT 2173

2008 ACAGAGAC G UUACUUGG 472 CCAAGTAA GGCTAGCTACAACGA GTCTCTGT 2174

2011 GAGACGUU A CUUGGAUU 473 AATCCAAG GGCTAGCTACAACGA AACGTCTC 2175

2017 UUACUUGG A UUUUACUG 474 CAGTAAAA GGCTAGCTACAACGA CCAAGTAA 2176

2022 UGGAUUUU A CUGCGGAC 475 GTCCGCAG GGCTAGCTACAACGA AAAATCCA 2177

2025 AUUUUACU G CGGACAGU 476 ACTGTCCG GGCTAGCTACAACGA AGTAAAAT 2178

2029 UACUGCGG A CAGUUAAU 477 ATTAACTG GGCTAGCTACAACGA CCGCAGTA 2179

2032 UGCGGACA G UUAAUAAC 478 GTTATTAA GGCTAGCTACAACGA TGTCCGCA 2180

2036 GACAGUUA A UAACAGAA 479 TTCTGTTA GGCTAGCTACAACGA TAACTGTC 2181

2039 AGUUAAUA A CAGAACAA 480 TTGTTCTG GGCTAGCTACAACGA TATTAACT 2182

2044 AUAACAGA A CAAUGCAC 481 GTGCATTG GGCTAGCTACAACGA TCTGTTAT 2183

2047 ACAGAACA A UGCACUAC 482 GTAGTGCA GGCTAGCTACAACGA TGTTCTGT 2184

2049 AGAACAAU G CACUACAG 483 CTGTAGTG GGCTAGCTACAACGA ATTGTTCT 2185

2051 AACAAUGC A CUACAGUA 484 TACTGTAG GGCTAGCTACAACGA GCATTGTT 2186

2054 AAUGCACU A CAGUAUUA 485 TAATACTG GGCTAGCTACAACGA AGTGCATT 2187

2057 GCACUACA G UAUUAGCA 486 TGCTAATA GGCTAGCTACAACGA TGTAGTGC 2188

2059 ACUACAGU A UUAGCAAG 487 CTTGCTAA GGCTAGCTACAACGA ACTGTAGT 2189

2063 CAGUAUUA G CAAGCAAA 488 TTTGCTTG GGCTAGCTACAACGA TAATACTG 2190

2067 AUUAGCAA G CAAAAAAU 489 ATTTTTTG GGCTAGCTACAACGA TTGCTAAT 2191

2074 AGCAAAAA A UGGCCAUC 490 GATGGCCA GGCTAGCTACAACGA TTTTTGCT 2192

2077 AAAAAAUG G CCAUCACU 491 AGTGATGG GGCTAGCTACAACGA CATTTTTT 2193

2080 AAAUGGCC A UCACUAAG 492 CTTAGTGA GGCTAGCTACAACGA GGCCATTT 2194

2083 UGGCCAUC A CUAAGGAG 493 CTCCTTAG GGCTAGCTACAACGA GATGGCCA 2195

2091 ACUAAGGA G CACUCCAU 494 ATGGAGTG GGCTAGCTACAACGA TCCTTAGT 2196

2093 UAAGGAGC A CUCCAUCA 495 TGATGGAG GGCTAGCTACAACGA GCTCCTTA 2197

2098 AGCACUCC A UCACUCUU 496 AAGAGTGA GGCTAGCTACAACGA GGAGTGCT 2198

2101 ACUCCAUC A CUCUUAAU 497 ATTAAGAG GGCTAGCTACAACGA GATGGAGT 2199

2108 CACUCUUA A UCUUACCA 498 TGGTAAGA GGCTAGCTACAACGA TAAGAGTG 2200

2113 UUAAUCUU A CCAUCAUG 499 CATGATGG GGCTAGCTACAACGA AAGATTAA 2201

2116 AUCUUACC A UCAUGAAU 500 ATTCATGA GGCTAGCTACAACGA GGTAAGAT 2202

2119 UUACCAUC A UGAAUGUU 501 AACATTCA GGCTAGCTACAACGA GATGGTAA 2203

2123 CAUCAUGA A UGUUUCCC 502 GGGAAACA GGCTAGCTACAACGA TCATGATG 2204

2125 UCAUGAAU G UUUCCCUG 503 GAGGGAAA GGCTAGCTACAACGA ATTCATGA 2205

2133 GUUUCCCU G CAAGAUUC 504 GAATCTTG GGCTAGCTACAACGA AGGGAAAC 2206

2138 CCUGCAAG A UUCAGGCA 505 TGCCTGAA GGCTAGCTACAACGA CTTGCAGG 2207

2144 AGAUUCAG G CACCUAUG 506 CATAGGTG GGCTAGCTACAACGA CTGAATCT 2208

2146 AUUCAGGC A CCUAUGCC 507 GGCATAGG GGCTAGCTACAACGA GCCTGAAT 2209

2150 AGGCACCU A UGCCUGCA 508 TGCAGGCA GGCTAGCTACAACGA AGGTGCCT 2210

2152 GCACCUAU G CCUGCAGA 509 TCTGCAGG GGCTAGCTACAACGA ATAGGTGC 2211

2156 CUAUGCCU G CAGAGCCA 510 TGGCTCTG GGCTAGCTACAACGA AGGCATAG 2212

2161 CCUGCAGA G CCAGGAAU 511 ATTCCTGG GGCTAGCTACAACGA TCTGCAGG 2213

2168 AGCCAGGA A UGUAUACA 512 TGTATACA GGCTAGCTACAACGA TCCTGGCT 2214

2170 CCAGGAAU G UAUACACA 513 TGTGTATA GGCTAGCTACAACGA ATTCCTGG 2215

2172 AGGAAUGU A UACACAGG 514 CCTGTGTA GGCTAGCTACAACGA ACATTCCT 2216

2174 GAAUGUAU A CACAGGGG 515 CCCCTGTG GGCTAGCTACAACGA ATACATTC 2217

2176 AUGUAUAC A CAGGGGAA 516 TTCCCCTG GGCTAGCTACAACGA GTATACAT 2218 2188 GGGAAGAA A UCCUCCAG 517 CTGGAGGA GGCTAGCTACAACGA TCTTCCC 2219

2206 AGAAAGAA A UUACAAUC 518 GATTGTAA GGCTAGCTACAACGA TTCTTTCT 2220

2209 AAGAAAUU A CAAUCAGA 519 TCTGATTG GGCTAGCTACAACGA AATTTCTT 2221

2212 AAAUUACA A UCAGAGAU 520 ATCTCTGA GGCTAGCTACAACGA TGTAATTT 2222

2219 AAUCAGAG A UCAGGAAG 521 CTTCCTGA GGCTAGCTACAACGA CTCTGATT 2223

2227 AUCAGGAA G CACCAUAC 522 GTATGGTG GGCTAGCTACAACGA TTCCTGAT 2224

2229 CAGGAAGC A CCAUACCU 523 AGGTATGG GGCTAGCTACAACGA GCTTCCTG 2225

2232 GAAGCACC A UACCUCCU 524 AGGAGGTA GGCTAGCTACAACGA GGTGCTTC 2226

2234 AGCACCAU A CCUCCUGC 525 GCAGGAGG GGCTAGCTACAACGA ATGGTGCT 2227

2241 UACCUCCU G CGAAACCU 526 AGGTTTCG GGCTAGCTACAACGA AGGAGGTA 2228

2246 CCUGCGAA A CCUCAGUG 527 CACTGAGG GGCTAGCTACAACGA TTCGCAGG 2229

2252 AAACCUCA G UGAUCACA 528 TGTGATCA GGCTAGCTACAACGA TGAGGTTT 2230

2255 CCUCAGUG A UCACACAG 529 CTGTGTGA GGCTAGCTACAACGA CACTGAGG 2231

2258 CAGUGAUC A CACAGUGG 530 CCACTGTG GGCTAGCTACAACGA GATCACTG 2232

2260 GUGAUCAC A CAGUGGCC 531 GGCCACTG GGCTAGCTACAACGA GTGATCAC 2233

2263 AUCACACA G UGGCCAUC 532 GATGGCCA GGCTAGCTACAACGA TGTGTGAT 2234

2266 ACACAGUG G CCAUCAGC 533 GCTGATGG GGCTAGCTACAACGA CACTGTGT 2235

2269 CAGUGGCC A UCAGCAGU 534 ACTGCTGA GGCTAGCTACAACGA GGCCACTG 2236

2273 GGCCAUCA G CAGUUCCA 535 TGGAACTG GGCTAGCTACAACGA TGATGGCC 2237

2276 CAUCAGCA G UUCCACCA 536 TGGTGGAA GGCTAGCTACAACGA TGCTGATG 2238

2281 GCAGUUCC A CCACUUUA 537 TAAAGTGG GGCTAGCTACAACGA GGAACTGC 2239

2284 GUUCCACC A CUUUAGAC 538 GTCTAAAG GGCTAGCTACAACGA GGTGGAAC 2240

2291 CACUUUAG A CUGUCAUG 539 CATGACAG GGCTAGCTACAACGA CTAAAGTG 2241

2294 UUUAGACU G UCAUGCUA 540 TAGCATGA GGCTAGCTACAACGA AGTCTAAA 2242

2297 AGACUGUC A UGCUAAUG 541 CATTAGCA GGCTAGCTACAACGA GACAGTCT 2243

2299 ACUGUCAU G CUAAUGGU 542 ACCATTAG GGCTAGCTACAACGA ATGACAGT 2244

2303 UCAUGCUA A UGGUGUCC 543 GGACACCA GGCTAGCTACAACGA TAGCATGA 2245

2306 UGCUAAUG G UGUCCCCG 544 CGGGGACA GGCTAGCTACAACGA CATTAGCA 2246

2308 CUAAUGGU G UCCCCGAG 545 CTCGGGGA GGCTAGCTACAACGA ACCATTAG 2247

2316 GUCCCCGA G CCUCAGAU 546 ATCTGAGG GGCTAGCTACAACGA TCGGGGAC 2248

2323 AGCCUCAG A UCACUUGG 547 CCAAGTGA GGCTAGCTACAACGA CTGAGGCT 2249

2326 CUCAGAUC A CUUGGUUU 548 AAACCAAG GGCTAGCTACAACGA GATCTGAG 2250

2331 AUCACUUG G UUUAAAAA 549 TTTTTAAA GGCTAGCTACAACGA CAAGTGAT 2251

2339 GUUUAAAA A CAACCACA 550 TGTGGTTG GGCTAGCTACAACGA TTTTAAAC 2252

2342 UAAAAACA A CCACAAAA 551 TTTTGTGG GGCTAGCTACAACGA TGTTTTTA 2253

2345 AAACAACC A CAAAAUAC 552 GTATTTTG GGCTAGCTACAACGA GGTTGTTT 2254

2350 ACCACAAA A UACAACAA 553 TTGTTGTA GGCTAGCTACAACGA TTTGTGGT 2255

2352 CACAAAAU A CAACAAGA 554 TCTTGTTG GGCTAGCTACAACGA ATTTTGTG 2256

2355 AAAAUACA A CAAGAGCC 555 GGCTCTTG GGCTAGCTACAACGA TGTATTTT 2257

2361 CAACAAGA G CCUGGAAU 556 ATTCCAGG GGCTAGCTACAACGA TCTTGTTG 2258

2368 AGCCUGGA A UUAUUUUA 557 TAAAATAA GGCTAGCTACAACGA TCCAGGCT 2259

2371 CUGGAAUU A UUUUAGGA 558 TCCTAAAA GGCTAGCTACAACGA AATTCCAG 2260

2379 AUUUUAGG A CCAGGAAG 559 CTTCCTGG GGCTAGCTACAACGA CCTAAAAT 2261

2387 ACCAGGAA G CAGCACGC 560 GCGTGCTG GGCTAGCTACAACGA TTCCTGGT 2262

2390 AGGAAGCA G CACGCUGU 561 ACAGCGTG GGCTAGCTACAACGA TGCTTCCT 2263

2392 GAAGCAGC A CGCUGUUU 562 AAACAGCG GGCTAGCTACAACGA GCTGCTTC 2264

2394 AGCAGCAC G CUGUUUAU 563 ATAAACAG GGCTAGCTACAACGA GTGCTGCT 2265

2397 AGCACGCU G UUUAUUGA 564 TCAATAAA GGCTAGCTACAACGA AGCGTGCT 2266

2401 CGCUGUUU A UUGAAAGA 565 TCTTTCAA GGCTAGCTACAACGA AAACAGCG 2267

2410 UUGAAAGA G UCACAGAA 566 TTCTGTGA GGCTAGCTACAACGA TCTTTCAA 2268

2413 AAAGAGUC A CAGAAGAG 567 CTCTTCTG GGCTAGCTACAACGA GACTCTTT 2269

2423 AGAAGAGG A UGAAGGUG 568 CACCTTCA GGCTAGCTACAACGA CCTCTTCT 2270 2429 GGAUGAAG G UGUCUAUC 569 GATAGACA GGCTAGCTACAACGA CTTCATCC 2271

2431 AUGAAGGU G UCUAUCAC 570 GTGATAGA GGCTAGCTACAACGA ACCTTCAT 2272

2435 AGGUGUCU A UCACUGCA 571 TGCAGTGA GGCTAGCTACAACGA AGACACCT 2273

2438 UGUCUAUC A CUGCAAAG 572 CTTTGCAG GGCTAGCTACAACGA GATAGACA 2274

2441 CUAUCACU G CAAAGCCA 573 TGGCTTTG GGCTAGCTACAACGA AGTGATAG 2275

2446 ACUGCAAA G CCACCAAC 574 GTTGGTGG GGCTAGCTACAACGA TTTGCAGT 2276

2449 GCAAAGCC A CCAACCAG 575 CTGGTTGG GGCTAGCTACAACGA GGCTTTGC 2277

2453 AGCCACCA A CCAGAAGG 576 CCTTCTGG GGCTAGCTACAACGA TGGTGGCT 2278

2462 CCAGAAGG G CUCUGUGG 577 CCACAGAG GGCTAGCTACAACGA CCTTCTGG 2279

2467 AGGGCUCU G UGGAAAGU 578 ACTTTCCA GGCTAGCTACAACGA AGAGCCCT 2280

2474 UGUGGAAA G UUCAGCAU 579 ATGCTGAA GGCTAGCTACAACGA TTTCCACA 2281

2479 AAAGUUCA G CAUACCUC 580 GAGGTATG GGCTAGCTACAACGA TGAACTTT 2282

2481 AGUUCAGC A UACCUCAC 581 GTGAGGTA GGCTAGCTACAACGA GCTGAACT 2283

2483 UUCAGCAU A CCUCAGUG 582 CAGTGAGG GGCTAGCTACAACGA ATGCTGAA 2284

2488 CAUACCUC A CUGUUCAA 583 TTGAACAG GGCTAGCTACAACGA GAGGTATG 2285

2491 ACCUCACU G UUCAAGGA 584 TCCTTGAA GGCTAGCTACAACGA AGTGAGGT 2286

2500 UUCAAGGA A CCUCGGAC 585 GTCCGAGG GGCTAGCTACAACGA TCCTTGAA 2287

2507 AACCUCGG A CAAGUCUA 586 TAGACTTG GGCTAGCTACAACGA CCGAGGTT 2288

2511 UCGGACAA G UCUAAUCU 587 AGATTAGA GGCTAGCTACAACGA TTGTCCGA 2289

2516 CAAGUCUA A UCUGGAGC 588 GCTCCAGA GGCTAGCTACAACGA TAGACTTG 2290

2523 AAUCUGGA G CUGAUCAC 589 GTGATCAG GGCTAGCTACAACGA TCCAGATT 2291

2527 UGGAGCUG A UCACUCUA 590 TAGAGTGA GGCTAGCTACAACGA CAGCTCCA 2292

2530 AGCUGAUC A CUCUAACA 591 TGTTAGAG GGCTAGCTACAACGA GATCAGCT 2293

2536 UCACUCUA A CAUGCACC 592 GGTGCATG GGCTAGCTACAACGA TAGAGTGA 2294

2538 ACUCUAAC A UGCACCUG 593 CAGGTGCA GGCTAGCTACAACGA GTTAGAGT 2295

2540 UCUAACAU G CACCUGUG 594 CACAGGTG GGCTAGCTACAACGA ATGTTAGA 2296

2542 UAACAUGC A CCUGUGUG 595 CACACAGG GGCTAGCTACAACGA GCATGTTA 2297

2546 AUGCACCU G UGUGGCUG 596 CAGCCACA GGCTAGCTACAACGA AGGTGCAT 2298

2548 GCACCUGU G UGGCUGCG 597 CGCAGCCA GGCTAGCTACAACGA ACAGGTGC 2299

2551 CCUGUGUG G CUGCGACU 598 AGTCGCAG GGCTAGCTACAACGA CACACAGG 2300

2554 GUGUGGCU G CGACUCUC 599 GAGAGTCG GGCTAGCTACAACGA AGCCACAC 2301

2557 UGGCUGCG A CUCUCUUC 600 GAAGAGAG GGCTAGCTACAACGA CGCAGCCA 2302

2568 CUCUUCUG G CUCCUAUU 601 AATAGGAG GGCTAGCTACAACGA CAGAAGAG 2303

2574 UGGCUCCU A UUAACCCU 602 AGGGTTAA GGCTAGCTACAACGA AGGAGCCA 2304

2578 UCCUAUUA A CCCUCCUU 603 AAGGAGGG GGCTAGCTACAACGA TAATAGGA 2305

2587 CCCUCCUU A UCCGAAAA 604 TTTTCGGA GGCTAGCTACAACGA AAGGAGGG 2306

2596 UCCGAAAA A UGAAAAGG 605 CCTTTTCA GGCTAGCTACAACGA TTTTCGGA 2307

2604 AUGAAAAG G UCUUCUUC 606 GAAGAAGA GGCTAGCTACAACGA CTTTTCAT 2308

2617 CUUCUGAA A UAAAGACU 607 AGTCTTTA GGCTAGCTACAACGA TTCAGAAG 2309

2623 AAAUAAAG A CUGACUAC 608 GTAGTCAG GGCTAGCTACAACGA CTTTATTT 2310

2627 AAAGACUG A CUACCUAU 609 ATAGGTAG GGCTAGCTACAACGA CAGTCTTT 2311

2630 GACUGACU A CCUAUCAA 610 TTGATAGG GGCTAGCTACAACGA AGTCAGTC 2312

2634 GACUACCU A UCAAUUAU 611 ATAATTGA GGCTAGCTACAACGA AGGTAGTC 2313

2638 ACCUAUCA A UUAUAAUG 612 CATTATAA GGCTAGCTACAACGA TGATAGGT 2314

2641 UAUCAAUU A UAAUGGAC 613 GTCCATTA GGCTAGCTACAACGA AATTGATA 2315

2644 CAAUUAUA A UGGACCCA 614 TGGGTCCA GGCTAGCTACAACGA TATAATTG 2316

2648 UAUAAUGG A CCCAGAUG 615 CATCTGGG GGCTAGCTACAACGA CCATTATA 2317

2654 GGACCCAG A UGAAGUUC 616 GAACTTCA GGCTAGCTACAACGA CTGGGTCC 2318

2659 CAGAUGAA G UUCCUUUG 617 CAAAGGAA GGCTAGCTACAACGA TTCATCTG 2319

2669 UCCUUUGG A UGAGCAGU 618 ACTGCTCA GGCTAGCTACAACGA CCAAAGGA 2320

2673 UUGGAUGA G CAGUGUGA 619 TCACACTG GGCTAGCTACAACGA TCATCCAA 2321

2676 GAUGAGCA G UGUGAGCG 620 CGCTCACA GGCTAGCTACAACGA TGCTCATC 2322 2678 UGAGCAGU G UGAGCGGC 621 GCCGCTCA GGCTAGCTACAACGA ACTGCTCA 2323

2682 CAGUGUGA G CGGCUCCC 622 GGGAGCCG GGCTAGCTACAACGA TCACACTG 2324

2685 UGUGAGCG G CUCCCUUA 623 TAAGGGAG GGCTAGCTACAACGA CGCTCACA 2325

2693 GCUCCCUU A UGAUGCCA 624 TGGCATCA GGCTAGCTACAACGA AAGGGAGC 2326

2696 CCCUUAUG A UGCCAGCA 625 TGCTGGCA GGCTAGCTACAACGA CATAAGGG 2327

2698 CUUAUGAU G CCAGCAAG 626 CTTGCTGG GGCTAGCTACAACGA ATCATAAG 2328

2702 UGAUGCCA G CAAGUGGG 627 CCCACTTG GGCTAGCTACAACGA TGGCATCA 2329

2706 GCCAGCAA G UGGGAGUU 628 AACTCCCA GGCTAGCTACAACGA TTGCTGGC 2330

2712 AAGUGGGA G UUUGCCCG 629 CGGGCAAA GGCTAGCTACAACGA TCCCACTT 2331

2716 GGGAGUUU G CCCGGGAG 630 CTCCCGGG GGCTAGCTACAACGA AAACTCCC 2332

2727 CGGGAGAG A CUUAAACU 631 AGTTTAAG GGCTAGCTACAACGA CTCTCCCG 2333

2733 AGACUUAA A CUGGGCAA 632 TTGCCCAG GGCTAGCTACAACGA TTAAGTCT 2334

2738 UAAACUGG G CAAAUCAC 633 GTGATTTG GGCTAGCTACAACGA CCAGTTTA 2335

2742 CUGGGCAA A UCACUUGG 634 CCAAGTGA GGCTAGCTACAACGA TTGCCCAG 2336

2745 GGCAAAUC A CUUGGAAG 635 CTTCCAAG GGCTAGCTACAACGA GATTTGCC 2337

2758 GAAGAGGG G CUUUUGGA 636 TCCAAAAG GGCTAGCTACAACGA CCCTCTTC 2338

2770 UUGGAAAA G UGGUUCAA 637 TTGAACCA GGCTAGCTACAACGA TTTTCCAA 2339

2773 GAAAAGUG G UUCAAGCA 638 TGCTTGAA GGCTAGCTACAACGA CACTTTTC 2340

2779 UGGUUCAA G CAUCAGCA 639 TGCTGATG GGCTAGCTACAACGA TTGAACCA 2341

2781 GUUCAAGC A UCAGCAUU 640 AATGCTGA GGCTAGCTACAACGA GCTTGAAC 2342

2785 AAGCAUCA G CAUUUGGC 641 GCCAAATG GGCTAGCTACAACGA TGATGCTT 2343

2787 GCAUCAGC A UUUGGCAU 642 ATGCCAAA GGCTAGCTACAACGA GCTGATGC 2344

2792 AGCAUUUG G CAUUAAGA 643 TCTTAATG GGCTAGCTACAACGA CAAATGCT 2345

2794 CAUUUGGC A UUAAGAAA 644 TTTCTTAA GGCTAGCTACAACGA GCCAAATG 2346

2802 AUUAAGAA A UCACCUAC 645 GTAGGTGA GGCTAGCTACAACGA TTCTTAAT 2347

2805 AAGAAAUC A CCUACGUG 646 CACGTAGG GGCTAGCTACAACGA GATTTCTT 2348

2809 AAUCACCU A CGUGCCGG 647 CCGGCACG GGCTAGCTACAACGA AGGTGATT 2349

2811 UCACCUAC G UGCCGGAC 648 GTCCGGCA GGCTAGCTACAACGA GTAGGTGA 2350

2813 ACCUACGU G CCGGACUG 649 CAGTCCGG GGCTAGCTACAACGA ACGTAGGT 2351

2818 CGUGCCGG A CUGUGGCU 650 AGCCACAG GGCTAGCTACAACGA CCGGCACG 2352

2821 GCCGGACU G UGGCUGUG 651 CACAGCCA GGCTAGCTACAACGA AGTCCGGC 2353

2824 GGACUGUG G CUGUGAAA 652 TTTCACAG GGCTAGCTACAACGA CACAGTCC 2354

2827 CUGUGGCU G UGAAAAUG 653 CATTTTCA GGCTAGCTACAACGA AGCCACAG 2355

2833 CUGUGAAA A UGCUGAAA 654 TTTCAGCA GGCTAGCTACAACGA TTTCACAG 2356

2835 GUGAAAAU G CUGAAAGA 655 TCTTTCAG GGCTAGCTACAACGA ATTTTCAC 2357

2848 AAGAGGGG G CCACGGCC 656 GGCCGTGG GGCTAGCTACAACGA CCCCTCTT 2358

2851 AGGGGGCC A CGGCCAGC 657 GCTGGCCG GGCTAGCTACAACGA GGCCCCCT 2359

2854 GGGCCACG G CCAGCGAG 658 CTCGCTGG GGCTAGCTACAACGA CGTGGCCC 2360

2858 CACGGCCA G CGAGUACA 659 TGTACTCG GGCTAGCTACAACGA TGGCCGTG 2361

2862 GCCAGCGA G UACAAAGC 660 GCTTTGTA GGCTAGCTACAACGA TCGCTGGC 2362

2864 CAGCGAGU A CAAAGCUC 661 GAGCTTTG GGCTAGCTACAACGA ACTCGCTG 2363

2869 AGUACAAA G CUCUGAUG 662 CATCAGAG GGCTAGCTACAACGA TTTGTACT 2364

2875 AAGCUCUG A UGACUGAG 663 CTCAGTCA GGCTAGCTACAACGA CAGAGCTT 2365

2878 CUCUGAUG A CUGAGCUA 664 TAGCTCAG GGCTAGCTACAACGA CATCAGAG 2366

2883 AUGACUGA G CUAAAAAU 665 ATTTTTAG GGCTAGCTACAACGA TCAGTCAT 2367

2890 AGCUAAAA A UCUUGACC 666 GGTCAAGA GGCTAGCTACAACGA TTTTAGCT 2368

2896 AAAUCUUG A CCCACAUU 667 AATGTGGG GGCTAGCTACAACGA CAAGATTT 2369

2900 CUUGACCC A CAUUGGCC 668 GGCCAATG GGCTAGCTACAACGA GGGTCAAG 2370

2902 UGACCCAC A UUGGCCAC 669 GTGGCCAA GGCTAGCTACAACGA GTGGGTCA 2371

2906 CCACAUUG G CCACCAUC 670 GATGGTGG GGCTAGCTACAACGA CAATGTGG 2372

2909 CAUUGGCC A CCAUCUGA 671 TCAGATGG GGCTAGCTACAACGA GGCCAATG 2373

2912 UGGCCACC A UCUGAACG 672 CGTTCAGA GGCTAGCTACAACGA GGTGGCCA 2374 2918 CCAUCUGA A CGUGGUUA 673 TAACCACG GGCTAGCTACAACGA TCAGATGG 2375

2920 AUCUGAAC G UGGUUAAC 674 GTTAACCA GGCTAGCTACAACGA GTTCAGAT 2376

2923 UGAACGUG G UUAACCUG 675 CAGGTTAA GGCTAGCTACAACGA CACGTTCA 2377

2927 CGUGGUUA A CCUGCUGG 676 CCAGCAGG GGCTAGCTACAACGA TAACCACG 2378

2931 GUUAACCU G CUGGGAGC 677 GCTCCCAG GGCTAGCTACAACGA AGGTTAAC 2379

2938 UGCUGGGA G CCUGCACC 678 GGTGCAGG GGCTAGCTACAACGA TCCCAGCA 2380

2942 GGGAGCCU G CACCAAGC 679 GCTTGGTG GGCTAGCTACAACGA AGGCTCCC 2381

2944 GAGCCUGC A CCAAGCAA 680 TTGCTTGG GGCTAGCTACAACGA GCAGGCTC 2382

2949 UGCACCAA G CAAGGAGG 681 CCTCCTTG GGCTAGCTACAACGA TTGGTGCA 2383

2958 CAAGGAGG G CCUCUGAU 682 ATCAGAGG GGCTAGCTACAACGA CCTCCTTG 2384

2965 GGCCUCUG A UGGUGAUU 683 AATCACCA GGCTAGCTACAACGA CAGAGGCC 2385

2968 CUCUGAUG G UGAUUGUU 684 AACAATCA GGCTAGCTACAACGA CATCAGAG 2386

2971 UGAUGGUG A UUGUUGAA 685 TTCAACAA GGCTAGCTACAACGA CACCATCA 2387

2974 UGGUGAUU G UUGAAUAC 686 GTATTCAA GGCTAGCTACAACGA AATCACCA 2388

2979 AUUGUUGA A UACUGCAA 687 TTGCAGTA GGCTAGCTACAACGA TCAACAAT 2389

2981 UGUUGAAU A CUGCAAAU 688 ATTTGCAG GGCTAGCTACAACGA ATTCAACA 2390

2984 UGAAUACU G CAAAUAUG 689 CATATTTG GGCTAGCTACAACGA AGTATTCA 2391

2988 UACUGCAA A UAUGGAAA 690 TTTCCATA GGCTAGCTACAACGA TTGCAGTA 2392

2990 CUGCAAAU A UGGAAAUC 691 GATTTCCA GGCTAGCTACAACGA ATTTGCAG 2393

2996 AUAUGGAA A UCUCUCCA 692 TGGAGAGA GGCTAGCTACAACGA TTCCATAT 2394

3005 UCUCUCCA A CUACCUCA 693 TGAGGTAG GGCTAGCTACAACGA TGGAGAGA 2395

3008 CUCCAACU A CCUCAAGA 694 TCTTGAGG GGCTAGCTACAACGA AGTTGGAG 2396

3017 CCUCAAGA G CAAACGUG 695 CACGTTTG GGCTAGCTACAACGA TCTTGAGG 2397

3021 AAGAGCAA A CGUGACUU 696 AAGTCACG GGCTAGCTACAACGA TTGCTCTT 2398

3023 GAGCAAAC G UGACUUAU 697 ATAAGTCA GGCTAGCTACAACGA GTTTGCTC 2399

3026 CAAACGUG A CUUAUUUU 698 AAAATAAG GGCTAGCTACAACGA CACGTTTG 2400

3030 CGUGACUU A UUUUUUCU 699 AGAAAAAA GGCTAGCTACAACGA AAGTCACG 2401

3041 UUUUCUCA A CAAGGAUG 700 CATCCTTG GGCTAGCTACAACGA TGAGAAAA 2402

3047 CAACAAGG A UGCAGCAC 701 GTGCTGCA GGCTAGCTACAACGA CCTTGTTG 2403

3049 ACAAGGAU G CAGCACUA 702 TAGTGCTG GGCTAGCTACAACGA ATCCTTGT 2404

3052 AGGAUGCA G CACUACAC 703 GTGTAGTG GGCTAGCTACAACGA TGCATCCT 2405

3054 GAUGCAGC A CUACACAU 704 ATGTGTAG GGCTAGCTACAACGA GCTGCATC 2406

3057 GCAGCACU A CACAUGGA 705 TCCATGTG GGCTAGCTACAACGA AGTGCTGC 2407

3059 AGCACUAC A CAUGGAGC 706 GCTCCATG GGCTAGCTACAACGA GTAGTGCT 2408

3061 CACUACAC A UGGAGCCU 707 AGGCTCCA GGCTAGCTACAACGA GTGTAGTG 2409

3066 CACAUGGA G CCUAAGAA 708 TTCTTAGG GGCTAGCTACAACGA TCCATGTG 2410

3082 AAGAAAAA A UGGAGCCA 709 TGGCTCCA GGCTAGCTACAACGA TTTTTCTT 2411

3087 AAAAUGGA G CCAGGCCU 710 AGGCCTGG GGCTAGCTACAACGA TCCATTTT 2412

3092 GGAGCCAG G CCUGGAAC 711 GTTCCAGG GGCTAGCTACAACGA CTGGCTCC 2413

3099 GGCCUGGA A CAAGGCAA 712 TTGCCTTG GGCTAGCTACAACGA TCCAGGCC 2414

3104 GGAACAAG G CAAGAAAC 713 GTTTCTTG GGCTAGCTACAACGA CTTGTTCC 2415

3111 GGGAAGAA A CCAAGACU 714 AGTCTTGG GGCTAGCTACAACGA TTCTTGCC 2416

3117 AAACCAAG A CUAGAUAG 715 CTATCTAG GGCTAGCTACAACGA CTTGGTTT 2417

3122 AAGACUAG A UAGCGUCA 716 TGACGCTA GGCTAGCTACAACGA CTAGTCTT 2418

3125 ACUAGAUA G CGUCACCA 717 TGGTGACG GGCTAGCTACAACGA TATCTAGT 2419

3127 UAGAUAGC G UCACCAGC 718 GCTGGTGA GGCTAGCTACAACGA GCTATCTA 2420

3130 AUAGCGUC A CCAGCAGC 719 GCTGCTGG GGCTAGCTACAACGA GACGCTAT 2421

3134 CGUCACCA G CAGCGAAA 720 TTTCGCTG GGCTAGCTACAACGA TGGTGACG 2422

3137 CACCAGCA G CGAAAGCU 721 AGGTTTCG GGCTAGCTACAACGA TGCTGGTG 2423

3143 CAGCGAAA G CUUUGCGA 722 TCGCAAAG GGCTAGCTACAACGA TTTCGCTG 2424

3148 AAAGCUUU G CGAGCUCC 723 GGAGCTCG GGCTAGCTACAACGA AAAGCTTT 2425

3152 CUUUGCGA G CUCCGGCU 724 AGCCGGAG GGCTAGCTACAACGA TCGCAAAG 2426 3158 GAGCUCCG G CUUUCAGG 725 CCTGAAAG GGCTAGCTACAACGA CGGAGCTC 2427

3170 UCAGGAAG A UAAAAGUC 726 GACTTTTA GGCTAGCTACAACGA CTTCCTGA 2428

3176 AGAUAAAA G UCUGAGUG 727 CACTCAGA GGCTAGCTACAACGA TTTTATCT 2429

3182 AAGUCUGA G UGAUGUUG 728 CAACATCA GGCTAGCTACAACGA TCAGACTT 2430

3185 UCUGAGUG A UGUUGAGG 729 CCTCAACA GGCTAGCTACAACGA CACTCAGA 2431

3187 UGAGUGAU G UUGAGGAA 730 TTCCTCAA GGCTAGCTACAACGA ATCACTCA 2432

3203 AGAGGAGG A UUCUGACG 731 CGTCAGAA GGCTAGCTACAACGA CCTCCTCT 2433

3209 GGAUUCUG A CGGUUUCU 732 AGAAACCG GGCTAGCTACAACGA CAGAATCC 2434

3212 UUCUGACG G UUUCUACA 733 TGTAGAAA GGCTAGCTACAACGA CGTCAGAA 2435

3218 CGGUUUCU A CAAGGAGC 734 GCTCCTTG GGCTAGCTACAACGA AGAAACCG 2436

3225 UACAAGGA G CCCAUCAC 735 GTGATGGG GGCTAGCTACAACGA TCCTTGTA 2437

3229 AGGAGCCC A UCACUAUG 736 CATAGTGA GGCTAGCTACAACGA GGGCTCCT 2438

3232 AGCCCAUC A CUAUGGAA 737 TTCCATAG GGCTAGCTACAACGA GATGGGCT 2439

3235 CCAUCACU A UGGAAGAU 738 ATCTTCCA GGCTAGCTACAACGA AGTGATGG 2440

3242 UAUGGAAG A UCUGAUUU 739 AAATCAGA GGCTAGCTACAACGA CTTCCATA 2441

3247 AAGAUCUG A UUUCUUAC 740 GTAAGAAA GGCTAGCTACAACGA CAGATCTT 2442

3254 GAUUUCUU A CAGUUUUC 741 GAAAACTG GGCTAGCTACAACGA AAGAAATC 2443

3257 UUCUUACA G UUUUCAAG 742 CTTGAAAA GGCTAGCTACAACGA TGTAAGAA 2444

3265 GUUUUCAA G UGGCCAGA 743 TCTGGCCA GGCTAGCTACAACGA TTGAAAAC 2445

3268 UUCAAGUG G CCAGAGGC 744 GCCTCTGG GGCTAGCTACAACGA CACTTGAA 2446

3275 GGCCAGAG G CAUGGAGU 745 ACTCCATG GGCTAGCTACAACGA CTCTGGCC 2447

3277 CCAGAGGC A UGGAGUUC 746 GAACTCCA GGCTAGCTACAACGA GCCTCTGG 2448

3282 GGCAUGGA G UUCCUGUC 747 GACAGGAA GGCTAGCTACAACGA TCCATGCC 2449

3288 GAGUUCCU G UCUUCCAG 748 CTGGAAGA GGCTAGCTACAACGA AGGAACTC 2450

3300 UCCAGAAA G UGCAUUCA 749 TGAATGCA GGCTAGCTACAACGA TTTCTGGA 2451

3302 CAGAAAGU G CAUUCAUC 750 GATGAATG GGCTAGCTACAACGA ACTTTCTG 2452

3304 GAAAGUGC A UUCAUCGG 751 CCGATGAA GGCTAGCTACAACGA GCACTTTC 2453

3308 GUGCAUUC A UCGGGACC 752 GGTCCCGA GGCTAGCTACAACGA GAATGCAC 2454

3314 UCAUCGGG A CCUGGCAG 753 CTGCCAGG GGCTAGCTACAACGA CCCGATGA 2455

3319 GGGACCUG G CAGCGAGA 754 TCTCGCTG GGCTAGCTACAACGA CAGGTCCC 2456

3322 ACCUGGCA G CGAGAAAC 755 GTTTCTCG GGCTAGCTACAACGA TGCCAGGT 2457

3329 AGCGAGAA A CAUUCUUU 756 AAAGAATG GGCTAGCTACAACGA TTCTCGCT 2458

3331 CGAGAAAC A UUCUUUUA 757 TAAAAGAA GGCTAGCTACAACGA GTTTCTCG 2459

3339 AUUCUUUU A UCUGAGAA 758 TTCTCAGA GGCTAGCTACAACGA AAAAGAAT 2460

3347 AUCUGAGA A CAACGUGG 759 CCACGTTG GGCTAGCTACAACGA TCTCAGAT 2461

3350 UGAGAACA A CGUGGUGA 760 TCACCACG GGCTAGCTACAACGA TGTTCTCA 2462

3352 AGAACAAC G UGGUGAAG 761 CTTCACCA GGCTAGCTACAACGA GTTGTTCT 2463

3355 ACAACGUG G UGAAGAUU 762 AATCTTCA GGCTAGCTACAACGA CACGTTGT 2464

3361 UGGUGAAG A UUUGUGAU 763 ATCACAAA GGCTAGCTACAACGA CTTCACCA 2465

3365 GAAGAUUU G UGAUUUUG 764 CAAAATCA GGCTAGCTACAACGA AAATCTTC 2466

3368 GAUUUGUG A UUUUGGCC 765 GGCCAAAA GGCTAGCTACAACGA CACAAATC 2467

3374 UGAUUUUG G CCUUGCCC 766 GGGCAAGG GGCTAGCTACAACGA CAAAATCA 2468

3379 UUGGCCUU G CCCGGGAU 767 ATCCCGGG GGCTAGCTACAACGA AAGGCCAA 2469

3386 UGCCCGGG A UAUUUAUA 768 TATAAATA GGCTAGCTACAACGA CCCGGGCA 2470

3388 CCCGGGAU A UUUAUAAG 769 CTTATAAA GGCTAGCTACAACGA ATCCCGGG 2471

3392 GGAUAUUU A UAAGAACC 770 GGTTCTTA GGCTAGCTACAACGA AAATATCC 2472

3398 UUAUAAGA A CCCCGAUU 771 AATCGGGG GGCTAGCTACAACGA TCTTATAA 2473

3404 GAACCCCG A UUAUGUGA 772 TCACATAA GGCTAGCTACAACGA CGGGGTTC 2474

3407 CCCCGAUU A UGUGAGAA 773 TTCTCACA GGCTAGCTACAACGA AATCGGGG 2475

3409 CCGAUUAU G UGAGAAAA 774 TTTTCTCA GGCTAGCTACAACGA ATAATCGG 2476

3422 AAAAGGAG A UACUCGAC 775 GTCGAGTA GGCTAGCTACAACGA CTCCTTTT 2477

3424 AAGGAGAU A CUCGACUU 776 AAGTCGAG GGCTAGCTACAACGA ATCTCCTT 2478 3429 GAUACUCG A CUUCCUCU 777 AGAGGAAG GGCTAGCTACAACGA CGAGTATC 2479

3441 CCUCUGAA A UGGAUGGC 778 GCCATCCA GGCTAGCTACAACGA TTCAGAGG 2480

3445 UGAAAUGG A UGGCUCCC 779 GGGAGCCA GGCTAGCTACAACGA CCATTTCA 2481

3448 AAUGGAUG G CUCCCGAA 780 TTCGGGAG GGCTAGCTACAACGA CATCCATT 2482

3456 GCUCCCGA A UCUAUCUU 781 AAGATAGA GGCTAGCTACAACGA TCGGGAGC 2483

3460 CCGAAUCU A UCUUUGAC 782 GTCAAAGA GGCTAGCTACAACGA AGATTCGG 2484

3467 UAUCUUUG A CAAAAUCU 783 AGATTTTG GGCTAGCTACAACGA CAAAGATA 2485

3472 UUGACAAA A UCUACAGC 784 GCTGTAGA GGCTAGCTACAACGA TTTGTCAA 2486

3476 CAAAAUCU A CAGCACCA 785 TGGTGCTG GGCTAGCTACAACGA AGATTTTG 2487

3479 AAUCUACA G CACCAAGA 786 TCTTGGTG GGCTAGCTACAACGA TGTAGATT 2488

3481 UCUACAGC A CCAAGAGC 787 GCTCTTGG GGCTAGCTACAACGA GCTGTAGA 2489

3488 CACCAAGA G CGACGUGU 788 ACACGTCG GGCTAGCTACAACGA TCTTGGTG 2490

3491 CAAGAGCG A CGUGUGGU 789 ACCACACG GGCTAGCTACAACGA CGCTCTTG 2491

3493 AGAGCGAC G UGUGGUCU 790 AGACCACA GGCTAGCTACAACGA GTCGCTCT 2492

3495 AGCGACGU G UGGUCUUA 791 TAAGACCA GGCTAGCTACAACGA ACGTCGCT 2493

3498 GACGUGUG G UCUUACGG 792 CCGTAAGA GGCTAGCTACAACGA CACACGTC 2494

3503 GUGGUCUU A CGGAGUAU 793 ATACTCCG GGCTAGCTACAACGA AAGACCAC 2495

3508 CUUACGGA G UAUUGCUG 794 CAGCAATA GGCTAGCTACAACGA TCCGTAAG 2496

3510 UACGGAGU A UUGCUGUG 795 CACAGCAA GGCTAGCTACAACGA ACTCCGTA 2497

3513 GGAGUAUU G CUGUGGGA 796 TCCCACAG GGCTAGCTACAACGA AATACTCC 2498

3516 GUAUUGCU G UGGGAAAU 797 ATTTCCCA GGCTAGCTACAACGA AGCAATAC 2499

3523 UGUGGGAA A UCUUCUCC 798 GGAGAAGA GGCTAGCTACAACGA TTCCCACA 2500

3536 CUCCUUAG G UGGGUCUC 799 GAGACCCA GGCTAGCTACAACGA CTAAGGAG 2501

3540 UUAGGUGG G UCUCCAUA 800 TATGGAGA GGCTAGCTACAACGA CCACCTAA 2502

3546 GGGUCUCC A UACCCAGG 801 CCTGGGTA GGCTAGCTACAACGA GGAGACCC 2503

3548 GUCUCCAU A CCCAGGAG 802 CTCCTGGG GGCTAGCTACAACGA ATGGAGAC 2504

3556 ACCCAGGA G UACAAAUG 803 CATTTGTA GGCTAGCTACAACGA TCCTGGGT 2505

3558 CCAGGAGU A CAAAUGGA 804 TCCATTTG GGCTAGCTACAACGA ACTCCTGG 2506

3562 GAGUACAA A UGGAUGAG 805 CTCATCCA GGCTAGCTACAACGA TTGTACTC 2507

3566 ACAAAUGG A UGAGGACU 806 AGTCCTCA GGCTAGCTACAACGA CCATTTGT 2508

3572 GGAUGAGG A CUUUUGCA 807 TGCAAAAG GGCTAGCTACAACGA CCTCATCC 2509

3578 GGACUUUU G CAGUCGCC 808 GGCGACTG GGCTAGCTACAACGA AAAAGTCC 2510

3581 CUUUUGCA G UCGCCUGA 809 TCAGGCGA GGCTAGCTACAACGA TGCAAAAG 2511

3584 UUGCAGUC G CCUGAGGG 810 CCCTCAGG GGCTAGCTACAACGA GACTGCAA 2512

3596 GAGGGAAG G CAUGAGGA 811 TCCTCATG GGCTAGCTACAACGA CTTCCCTC 2513

3598 GGGAAGGC A UGAGGAUG 812 CATCCTCA GGCTAGCTACAACGA GCCTTCCC 2514

3604 GCAUGAGG A UGAGAGCU 813 AGCTCTCA GGCTAGCTACAACGA CCTCATGC 2515

3610 GGAUGAGA G CUCCUGAG 814 CTCAGGAG GGCTAGCTACAACGA TCTCATCC 2516

3618 GCUCCUGA G UACUCUAC 815 GTAGAGTA GGCTAGCTACAACGA TCAGGAGC 2517

3620 UCCUGAGU A CUCUACUC 816 GAGTAGAG GGCTAGCTACAACGA ACTCAGGA 2518

3625 AGUACUCU A CUCCUGAA 817 TTCAGGAG GGCTAGCTACAACGA AGAGTACT 2519

3634 CUCCUGAA A UCUAUCAG 818 CTGATAGA GGCTAGCTACAACGA TTCAGGAG 2520

3638 UGAAAUCU A UCAGAUCA 819 TGATCTGA GGCTAGCTACAACGA AGATTTCA 2521

3643 UCUAUCAG A UCAUGCUG 820 CAGCATGA GGCTAGCTACAACGA CTGATAGA 2522

3646 AUCAGAUC A UGCUGGAC 821 GTCCAGCA GGCTAGCTACAACGA GATCTGAT 2523

3648 CAGAUCAU G CUGGACUG 822 CAGTCCAG GGCTAGCTACAACGA ATGATGTG 2524

3653 CAUGCUGG A CUGCUGGC 823 GCCAGCAG GGCTAGCTACAACGA CCAGCATG 2525

3656 GCUGGACU G CUGGCACA 824 TGTGCCAG GGCTAGCTACAACGA AGTCCAGC 2526

3660 GACUGCUG G CACAGAGA 825 TCTCTGTG GGCTAGCTACAACGA CAGCAGTC 2527

3662 CUGCUGGC A CAGAGACC 826 GGTCTCTG GGCTAGCTACAACGA GCCAGCAG 2528

3668 GCACAGAG A CCCAAAAG 827 CTTTTGGG GGCTAGCTACAACGA CTCTGTGC 2529

3681 AAAGAAAG G CCAAGAUU 828 AATCTTGG GGCTAGCTACAACGA CTTTCTTT 2530 3687 AGGCCAAG A UUUGCAGA 829 TCTGCAAA GGCTAGCTACAACGA CTTGGCCT 2531

3691 CAAGAUUU G CAGAACUU 830 AAGTTCTG GGCTAGCTACAACGA AAATCTTG 2532

3696 UUUGCAGA A CUUGUGGA 831 TCCACAAG GGCTAGCTACAACGA TCTGCAAA 2533

3700 CAGAACUU G UGGAAAAA 832 TTTTTCCA GGCTAGCTACAACGA AAGTTCTG 2534

3708 GUGGAAAA A CUAGGUGA 833 TCACCTAG GGCTAGCTACAACGA TTTTCCAC 2535

3713 AAAACUAG G UGAUUUGC 834 GCAAATCA GGCTAGCTACAACGA CTAGTTTT 2536

3716 ACUAGGUG A UUUGCUUC 835 GAAGCAAA GGCTAGCTACAACGA CACCTAGT 2537

3720 GGUGAUUU G CUUCAAGC 836 GCTTGAAG GGCTAGCTACAACGA AAATCACC 2538

3727 UGGUUCAA G CAAAUGUA 837 TACATTTG GGCTAGCTACAACGA TTGAAGCA 2539

3731 UCAAGCAA A UGUACAAC 838 GTTGTACA GGCTAGCTACAACGA TTGCTTGA 2540

3733 AAGCAAAU G UACAACAG 839 CTGTTGTA GGCTAGCTACAACGA ATTTGCTT 2541

3735 GCAAAUGU A CAACAGGA 840 TCCTGTTG GGCTAGCTACAACGA ACATTTGC 2542

3738 AAUGUACA A CAGGAUGG 841 CCATCCTG GGCTAGCTACAACGA TGTACATT 2543

3743 ACAACAGG A UGGUAAAG 842 CTTTACCA GGCTAGCTACAACGA CCTGTTGT 2544

3746 ACAGGAUG G UAAAGACU 843 AGTCTTTA GGCTAGCTACAACGA CATCCTGT 2545

3752 UGGUAAAG A CUACAUCC 844 GGATGTAG GGCTAGCTACAACGA CTTTACCA 2546

3755 UAAAGACU A CAUCCCAA 845 TTGGGATG GGCTAGCTACAACGA AGTCTTTA 2547

3757 AAGACUAC A UCCCAAUC 846 GATTGGGA GGCTAGCTACAACGA GTAGTCTT 2548

3763 ACAUCCCA A UCAAUGCC 847 GGCATTGA GGCTAGCTACAACGA TGGGATGT 2549

3767 CCCAAUCA A UGCCAUAC 848 GTATGGCA GGCTAGCTACAACGA TGATTGGG 2550

3769 CAAUCAAU G CCAUACUG 849 CAGTATGG GGCTAGCTACAACGA ATTGATTG 2551

3772 UCAAUGCC A UACUGACA 850 TGTCAGTA GGCTAGCTACAACGA GGCATTGA 2552

3774 AAUGCCAU A CUGACAGG 851 CCTGTCAG GGCTAGCTACAACGA ATGGCATT 2553

3778 CCAUACUG A CAGGAAAU 852 ATTTCCTG GGCTAGCTACAACGA CAGTATGG 2554

3785 GACAGGAA A UAGUGGGU 853 ACCCACTA GGCTAGCTACAACGA TTCCTGTC 2555

3788 AGGAAAUA G UGGGUUUA 854 TAAACCCA GGCTAGCTACAACGA TATTTCCT 2556

3792 AAUAGUGG G UUUACAUA 855 TATGTAAA GGCTAGCTACAACGA CCACTATT 2557

3796 GUGGGUUU A CAUACUCA 856 TGAGTATG GGCTAGCTACAACGA AAACCCAC 2558

3798 GGGUUUAC A UACUCAAC 857 GTTGAGTA GGCTAGCTACAACGA GTAAACCC 2559

3800 GUUUACAU A CUCAACUC 858 GAGTTGAG GGCTAGCTACAACGA ATGTAAAC 2560

3805 CAUACUCA A CUCCUGCC 859 GGCAGGAG GGCTAGCTACAACGA TGAGTATG 2561

3811 CAACUCCU G CCUUCUCU 860 AGAGAAGG GGCTAGCTACAACGA AGGAGTTG 2562

3824 CUCUGAGG A CUUCUUCA 861 TGAAGAAG GGCTAGCTACAACGA CCTCAGAG 2563

3839 CAAGGAAA G UAUUUCAG 862 CTGAAATA GGCTAGCTACAACGA TTTCCTTG 2564

3841 AGGAAAGU A UUUCAGCU 863 AGCTGAAA GGCTAGCTACAACGA ACTTTCCT 2565

3847 GUAUUUCA G CUCCGAAG 864 CTTCGGAG GGCTAGCTACAACGA TGAAATAC 2566

3855 GCUCCGAA G UUUAAUUC 865 GAATTAAA GGCTAGCTACAACGA TTCGGAGC 2567

3860 GAAGUUUA A UUCAGGAA 866 TTCCTGAA GGCTAGCTACAACGA TAAACTTC 2568

3869 UUCAGGAA G CUCUGAUG 867 CATCAGAG GGCTAGCTACAACGA TTCCTGAA 2569

3875 AAGCUCUG A UGAUGUCA 868 TGACATCA GGCTAGCTACAACGA CAGAGCTT 2570

3878 CUCUGAUG A UGUCAGAU 869 ATCTGACA GGCTAGCTACAACGA CATCAGAG 2571

3880 CUGAUGAU G UCAGAUAU 870 ATATCTGA GGCTAGCTACAACGA ATCATCAG 2572

3885 GAUGUCAG A UAUGUAAA 871 TTTACATA GGCTAGCTACAACGA CTGACATC 2573

3887 UGUCAGAU A UGUAAAUG 872 CATTTACA GGCTAGCTACAACGA ATCTGACA 2574

3889 UCAGAUAU G UAAAUGCU 873 AGCATTTA GGCTAGCTACAACGA ATATCTGA 2575

3893 AUAUGUAA A UGCUUUCA 874 TGAAAGCA GGCTAGCTACAACGA TTACATAT 2576

3895 AUGUAAAU G CUUUCAAG 875 CTTGAAAG GGCTAGCTACAACGA ATTTACAT 2577

3903 GCUUUCAA G UUCAUGAG 876 CTCATGAA GGCTAGCTACAACGA TTGAAAGC 2578

3907 UCAAGUUC A UGAGCCUG 877 CAGGCTCA GGCTAGCTACAACGA GAACTTGA 2579

3911 GUUCAUGA G CCUGGAAA 878 TTTCCAGG GGCTAGCTACAACGA TCATGAAC 2580

3922 UGGAAAGA A UCAAAACC 879 GGTTTTGA GGCTAGCTACAACGA TCTTTCCA 2581

3928 GAAUCAAA A CCUUUGAA 880 TTCAAAGG GGCTAGCTACAACGA TTTGATTC 2582 3939 UUUGAAGA A CUUUUACC 881 GGTAAAAG GGCTAGCTACAACGA TCTTCAAA 2583

3945 GAACUUUU A CCGAAUGC 882 GCATTCGG GGCTAGCTACAACGA AAAAGTTC 2584

3950 UUUACCGA A UGCCACCU 883 AGGTGGCA GGCTAGCTACAACGA TCGGTAAA 2585

3952 UACCGAAU G CCACCUCC 884 GGAGGTGG GGCTAGCTACAACGA ATTCGGTA 2586

3955 CGAAUGCC A CCUCCAUG 885 CATGGAGG GGCTAGCTACAACGA GGCATTCG 2587

3961 CCACCUCC A UGUUUGAU 886 ATCAAACA GGCTAGCTACAACGA GGAGGTGG 2588

3963 ACCUCCAU G UUUGAUGA 887 TCATCAAA GGCTAGCTACAACGA ATGGAGGT 2589

3968 CAUGUUUG A UGACUACC 888 GGTAGTCA GGCTAGCTACAACGA CAAACATG 2590

3971 GUUUGAUG A CUACCAGG 889 CCTGGTAG GGCTAGCTACAACGA CATCAAAC 2591

3974 UGAUGACU A CCAGGGCG 890 CGCCCTGG GGCTAGCTACAACGA AGTCATCA 2592

3980 CUACCAGG G CGACAGCA 891 TGCTGTCG GGCTAGCTACAACGA CCTGGTAG 2593

3983 CCAGGGCG A CAGCAGCA 892 TGCTGCTG GGCTAGCTACAACGA CGCCCTGG 2594

3986 GGGCGACA G CAGCACUC 893 GAGTGCTG GGCTAGCTACAACGA TGTCGCCC 2595

3989 CGACAGCA G CACUCUGU 894 ACAGAGTG GGCTAGCTACAACGA TGCTGTCG 2596

3991 ACAGCAGC A CUCUGUUG 895 CAACAGAG GGCTAGCTACAACGA GCTGCTGT 2597

3996 AGCACUCU G UUGGCCUC 896 GAGGCCAA GGCTAGCTACAACGA AGAGTGCT 2598

4000 CUCUGUUG G CCUCUCCC 897 GGGAGAGG GGCTAGCTACAACGA CAACAGAG 2599

4009 CCUCUCCC A UGCUGAAG 898 CTTCAGCA GGCTAGCTACAACGA GGGAGAGG 2600

4011 UCUCCCAU G CUGAAGCG 899 CGCTTCAG GGCTAGCTACAACGA ATGGGAGA 2601

4017 AUGCUGAA G CGCUUCAC 900 GTGAAGCG GGCTAGCTACAACGA TTCAGCAT 2602

4019 GCUGAAGC G CUUCACCU 901 AGGTGAAG GGCTAGCTACAACGA GCTTCAGC 2603

4024 AGCGCUUC A CCUGGACU 902 AGTCCAGG GGCTAGCTACAACGA GAAGCGCT 2604

4030 UCACCUGG A CUGACAGC 903 GCTGTCAG GGCTAGCTACAACGA CCAGGTGA 2605

4034 CUGGACUG A CAGCAAAC 904 GTTTGCTG GGCTAGCTACAACGA CAGTCCAG 2606.

4037 GACUGACA G GAAACCCA 905 TGGGTTTG GGCTAGCTACAACGA TGTCAGTC 2607

4041 GACAGGAA A CCCAAGGC 906 GCCTTGGG GGCTAGCTACAACGA TTGCTGTC 2608

4048 AACCCAAG G CCUCGCUC 907 GAGCGAGG GGCTAGCTACAACGA CTTGGGTT 2609

4053 AAGGCCUC G CUCAAGAU 908 ATCTTGAG GGCTAGCTACAACGA GAGGCCTT 2610

4060 CGCUCAAG A UUGACUUG 909 CAAGTCAA GGCTAGCTACAACGA CTTGAGCG 2611

4064 CAAGAUUG A CUUGAGAG 910 CTCTCAAG GGCTAGCTACAACGA CAATCTTG 2612

4072 ACUUGAGA G UAACCAGU 911 ACTGGTTA GGCTAGCTACAACGA TCTCAAGT 2613

4075 UGAGAGUA A CCAGUAAA 912 TTTACTGG GGCTAGCTACAACGA TACTCTCA 2614

4079 AGUAACCA G UAAAAGUA 913 TACTTTTA GGCTAGCTACAACGA TGGTTACT 2615

4085 CAGUAAAA G UAAGGAGU 914 ACTCCTTA GGCTAGCTACAACGA TTTTACTG 2616

4092 AGUAAGGA G UCGGGGCU 915 AGCCCCGA GGCTAGCTACAACGA TCCTTACT 2617

4098 GAGUCGGG G CUGUCUGA 916 TCAGACAG GGCTAGCTACAACGA CCCGACTC 2618

4101 UCGGGGCU G UCUGAUGU 917 ACATCAGA GGCTAGCTACAACGA AGCCCCGA 2619

4106 GCUGUCUG A UGUCAGCA 918 TGCTGACA GGCTAGCTACAACGA CAGACAGC 2620

4108 UGUCUGAU G UCAGCAGG 919 CCTGCTGA GGCTAGCTACAACGA ATCAGACA 2621

4112 UGAUGUCA G CAGGCCCA 920 TGGGCCTG GGCTAGCTACAACGA TGACATCA 2622

4116 GUCAGCAG G CCCAGUUU 921 AAACTGGG GGCTAGCTACAACGA CTGCTGAC 2623

4121 CAGGCCCA G UUUCUGCC 922 GGCAGAAA GGCTAGCTACAACGA TGGGCCTG 2624

4127 CAGUUUCU G CCAUUCCA 923 TGGAATGG GGCTAGCTACAACGA AGAAACTG 2625

4130 UUUCUGCC A UUCCAGCU 924 AGCTGGAA GGCTAGCTACAACGA GGCAGAAA 2626

4136 CCAUUCCA G CUGUGGGC 925 GCCCACAG GGCTAGCTACAACGA TGGAATGG 2627

4139 UUCCAGCU G UGGGCACG 926 CGTGCCCA GGCTAGCTACAACGA AGCTGGAA 2628

4143 AGCUGUGG G CACGUCAG 927 CTGACGTG GGCTAGCTACAACGA CCACAGCT 2629

4145 CUGUGGGC A CGUCAGCG 928 CGCTGACG GGCTAGCTACAACGA GCCCACAG 2630

4147 GUGGGCAC G UCAGCGAA 929 TTCGCTGA GGCTAGCTACAACGA GTGCCCAC 2631

4151 GCACGUCA G CGAAGGCA 930 TGCCTTCG GGCTAGCTACAACGA TGACGTGC 2632

4157 CAGCGAAG G CAAGCGCA 931 TGCGCTTG GGCTAGCTACAACGA CTTCGCTG 2633

4161 GAAGGCAA G CGCAGGUU 932 AACCTGCG GGCTAGCTACAACGA TTGCCTTC 2634 4163 AGGCAAGC G CAGGUUCA 933 TGAACCTG GGCTAGCTACAACGA GCTTGCCT 2635

4167 AAGCGCAG G UUCACCUA 934 TAGGTGAA GGCTAGCTACAACGA CTGCGCTT 2636

4171 GCAGGUUC A CCUACGAC 935 GTCGTAGG GGCTAGCTACAACGA GAACCTGC 2637

4175 GUUCACCU A CGACCACG 936 CGTGGTCG GGCTAGCTACAACGA AGGTGAAC 2638

4178 CACCUACG A CCACGCUG 937 CAGCGTGG GGCTAGCTACAACGA CGTAGGTG 2639

4181 CUACGACC A CGCUGAGC 938 GCTCAGCG GGCTAGCTACAACGA GGTCGTAG 2640

4183 ACGACCAC G CUGAGCUG 939 CAGCTCAG GGCTAGCTACAACGA GTGGTCGT 2641

4188 CACGCUGA G CUGGAAAG 940 CTTTCCAG GGCTAGCTACAACGA TCAGCGTG 2642

4201 AAAGGAAA A UCGCGUGC 941 GCACGCGA GGCTAGCTACAACGA TTTCCTTT 2643

4204 GGAAAAUC G CGUGCUGC 942 GCAGCACG GGCTAGCTACAACGA GATTTTCC 2644

4206 AAAAUCGC G UGCUGCUC 943 GAGCAGCA GGCTAGCTACAACGA GCGATTTT 2645

4208 AAUCGCGU G CUGCUCCC 944 GGGAGCAG GGCTAGCTACAACGA ACGCGATT 2646

4211 CGCGUGCU G CUCCCCGC 945 GCGGGGAG GGCTAGCTACAACGA AGCACGCG 2647

4218 UGCUCCCC G CCCCCAGA 946 TCTGGGGG GGCTAGCTACAACGA GGGGAGCA 2648

4226 GCCCCCAG A CUACAACU 947 AGTTGTAG GGCTAGCTACAACGA CTGGGGGC 2649

4229 CCCAGACU A CAACUCGG 948 CCGAGTTG GGCTAGCTACAACGA AGTCTGGG 2650

4232 AGACUACA A CUCGGUGG 949 CCACCGAG GGCTAGCTACAACGA TGTAGTCT 2651

4237 ACAACUCG G UGGUCCUG 950 CAGGACCA GGCTAGCTACAACGA CGAGTTGT 2652

4240 ACUCGGUG G UCCUGUAC 951 GTACAGGA GGCTAGCTACAACGA CACCGAGT 2653

4245 GUGGUCCU G UACUCCAC 952 GTGGAGTA GGCTAGCTACAACGA AGGACCAC 2654

4247 GGUCCUGU A CUCCACCC 953 GGGTGGAG GGCTAGCTACAACGA ACAGGACC 2655

4252 UGUACUCC A CCCCACCC 954 GGGTGGGG GGCTAGCTACAACGA GGAGTACA 2656

4257 UCCACCCC A CCCAUCUA 955 TAGATGGG GGCTAGCTACAACGA GGGGTGGA 2657

4261 CCCCACCC A UCUAGAGU 956 ACTCTAGA GGCTAGCTACAACGA GGGTGGGG 2658

4268 CAUCUAGA G UUUGACAC 957 GTGTCAAA GGCTAGCTACAACGA TCTAGATG 2659

4273 AGAGUUUG A CACGAAGC 958 GCTTCGTG GGCTAGCTACAACGA CAAACTCT 2660

4275 AGUUUGAC A CGAAGCCU 959 AGGCTTCG GGCTAGCTACAACGA GTCAAACT 2661

4280 GACACGAA G CCUUAUUU 960 AAATAAGG GGCTAGCTACAACGA TTCGTGTC 2662

4285 GAAGCCUU A UUUCUAGA 961 TCTAGAAA GGCTAGCTACAACGA AAGGCTTC 2663

4295 UUCUAGAA G CACAUGUG 962 CACATGTG GGCTAGCTACAACGA TTCTAGAA 2664

4297 CUAGAAGC A CAUGUGUA 963 TACACATG GGCTAGCTACAACGA GCTTCTAG 2665

4299 AGAAGCAC A UGUGUAUU 964 AATACACA GGCTAGCTACAACGA GTGCTTCT 2666

4301 AAGCACAU G UGUAUUUA 965 TAAATACA GGCTAGCTACAACGA ATGTGCTT 2667

4303 GCACAUGU G UAUUUAUA 966 TATAAATA GGCTAGCTACAACGA ACATGTGC 2668

4305 ACAUGUGU A UUUAUACC 967 GGTATAAA GGCTAGCTACAACGA ACACATGT 2669

4309 GUGUAUUU A UACCCCCA 968 TGGGGGTA GGCTAGCTACAACGA AAATACAC 2670

4311 GUAUUUAU A CCCCCAGG 969 CCTGGGGG GGCTAGCTACAACGA ATAAATAC 2671

4322 CCCAGGAA A CUAGCUUU 970 AAAGCTAG GGCTAGCTACAACGA TTCCTGGG 2672

4326 GGAAACUA G CUUUUGCC 971 GGCAAAAG GGCTAGCTACAACGA TAGTTTCC 2673

4332 UAGCUUUU G CCAGUAUU 972 AATACTGG GGCTAGCTACAACGA AAAAGCTA 2674

4336 UUUUGCCA G UAUUAUGC 973 GCATAATA GGCTAGCTACAACGA TGGCAAAA 2675

4338 UUGCCAGU A UUAUGCAU 974 ATGCATAA GGCTAGCTACAACGA ACTGGCAA 2676

4341 CCAGUAUU A UGCAUAUA 975 TATATGCA GGCTAGCTACAACGA AATACTGG 2677

4343 AGUAUUAU G CAUAUAUA 976 TATATATG GGCTAGCTACAACGA ATAATACT 2678

4345 UAUUAUGC A UAUAUAAG 977 CTTATATA GGCTAGCTACAACGA GCATAATA 2679

4347 UUAUGCAU A UAUAAGUU 978 AACTTATA GGCTAGCTACAACGA ATGCATAA 2680

4349 AUGCAUAU A UAAGUUUA 979 TAAACTTA GGCTAGCTACAACGA ATATGCAT 2681

4353 AUAUAUAA G UUUACACC 980 GGTGTAAA GGCTAGCTACAACGA TTATATAT 2682

4357 AUAAGUUU A CACCUUUA 981 TAAAGGTG GGCTAGCTACAACGA AAACTTAT 2683

4359 AAGUUUAC A CCUUUAUC 982 GATAAAGG GGCTAGCTACAACGA GTAAACTT 2684

4365 ACACCUUU A UCUUUCCA 983 TGGAAAGA GGCTAGCTACAACGA AAAGGTGT 2685

4373 AUCUUUCC A UGGGAGCC 984 GGCTCCCA GGCTAGCTACAACGA GGAAAGAT 2686 4379 CCAUGGGA G CCAGCUGC 985 GCAGCTGG GGCTAGCTACAACGA TCCCATGG 2687

4383 GGGAGCCA G CUGCUUUU 986 AAAAGCAG GGCTAGCTACAACGA TGGCTCCC 2688

4386 AGCCAGCU G CUUUUUGU 987 ACAAAAAG GGCTAGCTACAACGA AGCTGGCT 2689

4393 UGCUUUUU G UGAUUUUU 988 AAAAATCA GGCTAGCTACAACGA AAAAAGCA 2690

4396 UUUUUGUG A UUUUUUUA 989 TAAAAAAA GGCTAGCTACAACGA CACAAAAA 2691

4405 UUUUUUUA A UAGUGCUU 990 AAGCACTA GGCTAGCTACAACGA TAAAAAAA 2692

4408 UUUUAAUA G UGCUUUUU 991 AAAAAGCA GGCTAGCTACAACGA TATTAAAA 2693

4410 UUAAUAGU G CUUUUUϋU 992 AAAAAAAG GGCTAGCTACAACGA ACTATTAA 2694

4424 UUUUUUUG A CUAACAAG 993 CTTGTTAG GGCTAGCTACAACGA CAAAAAAA 2695

4428 UUUGACUA A CAAGAAUG 994 CATTCTTG GGCTAGCTACAACGA TAGTCAAA 2696

4434 UAACAAGA A UGUAACUC 995 GAGTTACA GGCTAGCTACAACGA TCTTGTTA 2697

4436 ACAAGAAU G UAACUCCA 996 TGGAGTTA GGCTAGCTACAACGA ATTCTTGT 2698

4439 AGAAUGUA A CUCCAGAU 997 ATCTGGAG GGCTAGCTACAACGA TACATTCT 2699

4446 AACUCCAG A UAGAGAAA 998 TTTCTCTA GGCTAGCTACAACGA CTGGAGTT 2700

4454 AUAGAGAA A UAGUGACA 999 TGTCACTA GGCTAGCTACAACGA TTCTCTAT 2701

4457 GAGAAAUA G UGACAAGU 1000 ACTTGTCA GGCTAGCTACAACGA TATTTCTC 2702

4460 AAAUAGUG A CAAGUGAA 1001 TTCACTTG GGCTAGCTACAACGA CACTATTT 2703

4464 AGUGACAA G UGAAGAAC 1002 GTTCTTCA GGCTAGCTACAACGA TTGTCACT 2704

4471 AGUGAAGA A CACUACUG 1003 CAGTAGTG GGCTAGCTACAACGA TCTTCACT 2705

4473 UGAAGAAC A CUACUGCU 1004 AGCAGTAG GGCTAGCTACAACGA GTTCTTCA 2706

4476 AGAACACU A CUGCUAAA 1005 TTTAGCAG GGCTAGCTACAACGA AGTGTTCT 2707

4479 ACACUACU G CUAAAUCC 1006 GGATTTAG GGCTAGCTACAACGA AGTAGTGT 2708

4484 ACUGCUAA A UCCUCAUG 1007 CATGAGGA GGCTAGCTACAACGA TTAGCAGT 2709

4490 AAAUCCUC A UGUUACUC 1008 GAGTAACA GGCTAGCTACAACGA GAGGATTT 2710

4492 AUCCUCAU G UUACUCAG 1009 CTGAGTAA GGCTAGCTACAACGA ATGAGGAT 2711

4495 CUCAUGUU A CUCAGUGU 1010 ACACTGAG GGCTAGCTACAACGA AACATGAG 2712

4500 GUUACUCA G UGUUAGAG 1011 CTCTAACA GGCTAGCTACAACGA TGAGTAAC 2713

4502 UACUCAGU G UUAGAGAA 1012 TTCTCTAA GGCTAGCTACAACGA ACTGAGTA 2714

4511 UUAGAGAA A UCCUUCCU 1013 AGGAAGGA GGCTAGCTACAACGA TTCTCTAA 2715

4522 CUUCCUAA A CCCAAUGA 1014 TCATTGGG GGCTAGCTACAACGA TTAGGAAG 2716

4527 UAAACCCA A UGACUUCC 1015 GGAAGTCA GGCTAGCTACAACGA TGGGTTTA 2717

4530 ACCCAAUG A CUUCCCUG 1016 CAGGGAAG GGCTAGCTACAACGA CATTGGGT 2718

4538 ACUUCCCU G CUCCAACC 1017 GGTTGGAG GGCTAGCTACAACGA AGGGAAGT 2719

4544 CUGCUCCA A CCCCCGCC 1018 GGCGGGGG GGCTAGCTACAACGA TGGAGCAG 2720

4550 CAACCCCC G CCACCUCA 1019 TGAGGTGG GGCTAGCTACAACGA GGGGGTTG 2721

4553 CCCCCGCC A CCUCAGGG 1020 CCCTGAGG GGCTAGCTACAACGA GGCGGGGG 2722

4561 ACCUCAGG G CACGCAGG 1021 CCTGCGTG GGCTAGCTACAACGA CCTGAGGT 2723

4563 CUCAGGGC A CGCAGGAC 1022 GTCCTGCG GGCTAGCTACAACGA GCCCTGAG 2724

4565 CAGGGCAC G CAGGACCA 1023 TGGTCCTG GGCTAGCTACAACGA GTGCCCTG 2725

4570 CACGCAGG A CCAGUUUG 1024 CAAACTGG GGCTAGCTACAACGA CCTGCGTG 2726

4574 CAGGACCA G UUUGAUUG 1025 CAATCAAA GGCTAGCTACAACGA TGGTCCTG 2727

4579 CCAGUUUG A UUGAGGAG 1026 CTCCTCAA GGCTAGCTACAACGA CAAACTGG 2728

4587 AUUGAGGA G CUGCACUG 1027 CAGTGCAG GGCTAGCTACAACGA TCCTCAAT 2729

4590 GAGGAGCU G CACUGAUC 1028 GATCAGTG GGCTAGCTACAACGA AGCTCCTC 2730

4592 GGAGCUGC A CUGAUCAC 1029 GTGATCAG GGCTAGCTACAACGA GCAGCTCC 2731

4596 CUGCACUG A UCACCCAA 1030 TTGGGTGA GGCTAGCTACAACGA CAGTGCAG 2732

4599 CACUGAUC A CCCAAUGC 1031 GCATTGGG GGCTAGCTACAACGA GATCAGTG 2733

4604 AUCACCCA A UGCAUCAC 1032 GTGATGCA GGCTAGCTACAACGA TGGGTGAT 2734

4606 CACCCAAU G CAUCACGU 1033 ACGTGATG GGCTAGCTACAACGA ATTGGGTG 2735

4608 CCCAAUGC A UCACGUAC 1034 GTACGTGA GGCTAGCTACAACGA GCATTGGG 2736

4611 AAUGCAUC A CGUACCCC 1035 GGGGTACG GGCTAGCTACAACGA GATGCATT 2737

4613 UGCAUCAC G UACCCCAC 1036 GTGGGGTA GGCTAGCTACAACGA GTGATGCA 2738 4615 CAUCACGU A CCCCACUG 1037 CAGTGGGG GGCTAGCTACAACGA ACGTGATG 2739

4620 CGUACCCC A CUGGGCCA 1038 TGGCCCAG GGCTAGCTACAACGA GGGGTACG 2740

4625 CCCACUGG G CCAGCCCU 1039 AGGGCTGG GGCTAGCTACAACGA CCAGTGGG 2741

4629 CUGGGCCA G CCCUGCAG 1040 CTGCAGGG GGCTAGCTACAACGA TGGCCCAG 2742

4634 CCAGCCCU G CAGCCCAA 1041 TTGGGCTG GGCTAGCTACAACGA AGGGCTGG 2743

4637 GCCCUGCA G CCCAAAAC 1042 GTTTTGGG GGCTAGCTACAACGA TGCAGGGC 2744

4644 AGCCCAAA A CCCAGGGC 1043 GCCCTGGG GGCTAGCTACAACGA TTTGGGCT 2745

4651 AACCCAGG G CAACAAGC 1044 GCTTGTTG GGCTAGCTACAACGA CCTGGGTT 2746

4654 CCAGGGCA A CAAGCCCG 1045 CGGGCTTG GGCTAGCTACAACGA TGCCCTGG 2747

4658 GGCAACAA G CCCGUUAG 1046 CTAACGGG GGCTAGCTACAACGA TTGTTGCC 2748

4662 ACAAGCCC G UUAGCCCC 1047 GGGGCTAA GGCTAGCTACAACGA GGGCTTGT 2749

4666 GCCCGUUA G CCCCAGGG 1048 CCCTGGGG GGCTAGCTACAACGA TAACGGGC 2750

4676 CCCAGGGG A UCACUGGC 1049 GCCAGTGA GGCTAGCTACAACGA CCCCTGGG 2751

4679 AGGGGAUC A CUGGCUGG 1050 CCAGCCAG GGCTAGCTACAACGA GATCCCCT 2752

4683 GAUCACUG G CUGGCCUG 1051 CAGGCCAG GGCTAGCTACAACGA CAGTGATC 2753

4687 ACUGGCUG G CCUGAGCA 1052 TGCTCAGG GGCTAGCTACAACGA CAGCCAGT 2754

4693 UGGCCUGA G CAACAUCU 1053 AGATGTTG GGCTAGCTACAACGA TCAGGCCA 2755

4696 CCUGAGCA A CAUCUCGG 1054 CCGAGATG GGCTAGCTACAACGA TGCTCAGG 2756

4698 UGAGCAAC A UCUCGGGA 1055 TCCCGAGA GGCTAGCTACAACGA GTTGCTCA 2757

4707 UCUCGGGA G UCCUCUAG 1056 CTAGAGGA GGCTAGCTACAACGA TCCCGAGA 2758

4715 GUCCUCUA G CAGGCCUA 1057 TAGGCCTG GGCTAGCTACAACGA TAGAGGAC 2759

4719 UCUAGCAG G CCUAAGAC 1058 GTCTTAGG GGCTAGCTACAACGA CTGCTAGA 2760

4726 GGCCUAAG A CAUGUGAG 1059 CTCACATG GGCTAGCTACAACGA CTTAGGCC 2761

4728 CCUAAGAC A UGUGAGGA 1060 TCCTCACA GGCTAGCTACAACGA GTCTTAGG 2762

4730 UAAGACAU G UGAGGAGG 1061 CCTCCTCA GGCTAGCTACAACGA ATGTCTTA 2763

4752 GAAAAAAA G CAAAAAGC 1062 GCTTTTTG GGCTAGCTACAACGA TTTTTTTC 2764

4759 AGCAAAAA G CAAGGGAG 1063 CTCCCTTG GGCTAGCTACAACGA TTTTTGCT 2765

4777 AAAGAGAA A CCGGGAGA 1064 TCTCCCGG GGCTAGCTACAACGA TTCTCTTT 2766

4788 GGGAGAAG G CAUGAGAA 1065 TTCTCATG GGCTAGCTACAACGA CTTCTCCC 2767

4790 GAGAAGGC A UGAGAAAG 1066 CTTTCTCA GGCTAGCTACAACGA GCCTTCTC 2768

4800 GAGAAAGA A UUUGAGAC 1067 GTCTCAAA GGCTAGCTACAACGA TCTTTCTC 2769

4807 AAUUUGAG A CGCACCAU 1068 ATGGTGCG GGCTAGCTACAACGA CTCAAATT 2770

4809 UUUGAGAC G CACCAUGU 1069 ACATGGTG GGCTAGCTACAACGA GTCTCAAA 2771

4811 UGAGACGC A CCAUGUGG 1070 CCACATGG GGCTAGCTACAACGA GCGTCTCA 2772

4814 GACGCACC A UGUGGGCA 1071 TGCCCACA GGCTAGCTACAACGA GGTGCGTC 2773

4816 CGCACCAU G UGGGCACG 1072 CGTGCCCA GGCTAGCTACAACGA ATGGTGCG 2774

4820 CCAUGUGG G CACGGAGG 1073 CCTGCGTG GGCTAGCTACAACGA CCACATGG 2775

4822 AUGUGGGC A CGGAGGGG 1074 CCCCTCCG GGCTAGCTACAACGA GCCCACAT 2776

4832 GGAGGGGG A CGGGGCUC 1075 GAGCCCCG GGCTAGCTACAACGA CCCCCTCC 2777

4837 GGGACGGG G CUCAGCAA 1076 TTGCTGAG GGCTAGCTACAACGA CCCGTCCC 2778

4842 GGGGCUCA G CAAUGCCA 1077 TGGCATTG GGCTAGCTACAACGA TGAGCCCC 2779

4845 GCUCAGCA A UGCCAUUU 1078 AAATGGCA GGCTAGCTACAACGA TGCTGAGC 2780

4847 UCAGCAAU G CCAUUUCA 1079 TGAAATGG GGCTAGCTACAACGA ATTGCTGA 2781

4850 GCAAUGCC A UUUCAGUG 1080 CACTGAAA GGCTAGCTACAACGA GGCATTGC 2782

4856 CCAUUUCA G UGGCUUCC 1081 GGAAGCCA GGCTAGCTACAACGA TGAAATGG 2783

4859 UUUCAGUG G CUUCCCAG 1082 CTGGGAAG GGCTAGCTACAACGA CACTGAAA 2784

4867 GCUUCCCA G CUCUGACC 1083 GGTCAGAG GGCTAGCTACAACGA TGGGAAGC 2785

4873 CAGCUCUG A CCCUUCUA 1084 TAGAAGGG GGCTAGCTACAACGA CAGAGCTG 2786

4881 ACCCUUCU A CAUUUGAG 1085 CTCAAATG GGCTAGCTACAACGA AGAAGGGT 2787

4883 CCUUCUAC A UUUGAGGG 1086 CCCTCAAA GGCTAGCTACAACGA GTAGAAGG 2788

4891 AUUUGAGG G CCCAGCCA 1087 TGGCTGGG GGCTAGCTACAACGA CCTCAAAT 2789

4896 AGGGCCCA G CCAGGAGC 1088 GCTCCTGG GGCTAGCTACAACGA TGGGCCCT 2790 4903 AGCCAGGA G CAGAUGGA 1089 TCCATCTG GGCTAGCTACAACGA TCCTGGCT 2791

4907 AGGAGCAG A UGGACAGC 1090 GCTGTCCA GGCTAGCTACAACGA CTGCTCCT 2792

4911 GCAGAUGG A CAGCGAUG 1091 CATCGCTG GGCTAGCTACAACGA CCATCTGC 2793

4914 GAUGGACA G CGAUGAGG 1092 CCTCATCG GGCTAGCTACAACGA TGTCCATC 2794

4917 GGACAGCG A UGAGGGGA 1093 TCCCCTCA GGCTAGCTACAACGA CGCTGTCC 2795

4925 AUGAGGGG A CAUUUUCU 1094 AGAAAATG GGCTAGCTACAACGA CCCCTCAT 2796

4927 GAGGGGAC A UUUUCUGG 1095 CCAGAAAA GGCTAGCTACAACGA GTCCCCTC 2797

4936 UUUUCUGG A UUCUGGGA 1096 TCCCAGAA GGCTAGCTACAACGA CCAGAAAA 2798

4946 UCUGGGAG G CAAGAAAA 1097 TTTTCTTG GGCTAGCTACAACGA CTCCCAGA 2799

4957 AGAAAAGG A CAAAUAUC 1098 GATATTTG GGCTAGCTACAACGA CCTTTTCT 2800

4961 AAGGACAA A UAUCUUUU 1099 AAAAGATA GGCTAGCTACAACGA TTGTCCTT 2801

4963 GGACAAAU A UCUUUUUU 1100 AAAAAAGA GGCTAGCTACAACGA ATTTGTCC 2802

4975 UUUUUGGA A CUAAAGCA 1101 TGCTTTAG GGCTAGCTACAACGA TCCAAAAA 2803

4981 GAACUAAA G CAAAUUUU 1102 AAAATTTG GGCTAGCTACAACGA TTTAGTTC 2804

4985 UAAAGCAA A UUUUAGAC 1103 GTCTAAAA GGCTAGCTACAACGA TTGCTTTA 2805

4992 AAUUUUAG A CCUUUACC 1104 GGTAAAGG GGCTAGCTACAACGA CTAAAATT 2806

4998 AGACCUUU A CCUAUGGA 1105 TCCATAGG GGCTAGCTACAACGA AAAGGTCT 2807

5002 CUUUACCU A UGGAAGUG 1106 CACTTCCA GGCTAGCTACAACGA AGGTAAAG 2808

5008 CUAUGGAA G UGGUUCUA 1107 TAGAACCA GGCTAGCTACAACGA TTCCATAG 2809

5011 UGGAAGUG G UUCUAUGU 1108 ACATAGAA GGCTAGCTACAACGA CACTTCCA 2810

5016 GUGGUUCU A UGUCCAUU 1109 AATGGACA GGCTAGCTACAACGA AGAACCAC 2811

5018 GGUUCUAU G UCCAUUCU 1110 AGAATGGA GGCTAGCTACAACGA ATAGAACC 2812

5022 CUAUGUCC A UUCUCAUU 1111 AATGAGAA GGCTAGCTACAACGA GGACATAG 2813

5028 CCAUUCUC A UUCGUGGC 1112 GCCACGAA GGCTAGCTACAACGA GAGAATGG 2814

5032 UCUCAUUC G UGGCAUGU 1113 ACATGCCA GGCTAGCTACAACGA GAATGAGA 2815

5035 CAUUCGUG G CAUGUUUU 1114 AAAACATG GGCTAGCTACAACGA CACGAATG 2816

5037 UUCGUGGC A UGUUUUGA 1115 TCAAAACA GGCTAGCTACAACGA GCCACGAA 2817

5039 CGUGGCAU G UUUUGAUU 1116 AATCAAAA GGCTAGCTACAACGA ATGCCACG 2818

5045 AUGUUUUG A UUUGUAGC 1117 GCTACAAA GGCTAGCTACAACGA CAAAACAT 2819

5049 UUUGAUUU G UAGCACUG 1118 CAGTGCTA GGCTAGCTACAACGA AAATCAAA 2820

5052 GAUUUGUA G CACUGAGG 1119 CCTCAGTG GGCTAGCTACAACGA TACAAATC 2821

5054 UUUGUAGC A CUGAGGGU 1120 ACCCTCAG GGCTAGCTACAACGA GCTACAAA 2822

5061 CACUGAGG G UGGCACUC 1121 GAGTGCCA GGCTAGCTACAACGA CCTCAGTG 2823

5064 UGAGGGUG G CACUCAAC 1122 GTTGAGTG GGCTAGCTACAACGA CACCCTCA 2824

5066 AGGGUGGC A CUCAACUC 1123 GAGTTGAG GGCTAGCTACAACGA GCCACCCT 2825

5071 GGCACUCA A CUCUGAGC 1124 GGTCAGAG GGCTAGCTACAACGA TGAGTGCC 2826

5078 AACUCUGA G CCCAUACU 1125 AGTATGGG GGCTAGCTACAACGA TCAGAGTT 2827

5082 CUGAGCCC A UACUUUUG 1126 CAAAAGTA GGCTAGCTACAACGA GGGCTCAG 2828

5084 GAGCCCAU A CUUUUGGC 1127 GCCAAAAG GGCTAGCTACAACGA ATGGGCTC 2829

5091 UACUUUUG G CUCCUCUA 1128 TAGAGGAG GGCTAGCTACAACGA CAAAAGTA 2830

5100 CUCCUCUA G UAAGAUGC 1129 GCATCTTA GGCTAGCTACAACGA TAGAGGAG 2831

5105 CUAGUAAG A UGCACUGA 1130 TCAGTGCA GGCTAGCTACAACGA CTTACTAG 2832

5107 AGUAAGAU G CACUGAAA 1131 TTTCAGTG GGCTAGCTACAACGA ATCTTACT 2833

5109 UAAGAUGC A CUGAAAAC 1132 GTTTTCAG GGCTAGCTACAACGA GCATCTTA 2834

5116 CACUGAAA A CUUAGCCA 1133 TGGCTAAG GGCTAGCTACAACGA TTTCAGTG 2835

5121 AAAACUUA G CCAGAGUU 1134 AACTCTGG GGCTAGCTACAACGA TAAGTTTT 2836

5127 UAGCCAGA G UUAGGUUG 1135 CAACCTAA GGCTAGCTACAACGA TCTGGCTA 2837

5132 AGAGUUAG G UUGUCUCC 1136 GGAGACAA GGCTAGCTACAACGA CTAACTCT 2838

5135 GUUAGGUU G UCUCCAGG 1137 CCTGGAGA GGCTAGCTACAACGA AACCTAAC 2839

5143 GUCUCCAG G CCAUGAUG 1138 CATCATGG GGCTAGCTACAACGA CTGGAGAC 2840

5146 UCCAGGCC A UGAUGGCC 1139 GGCCATCA GGCTAGCTACAACGA GGCCTGGA 2841

5149 AGGCCAUG A UGGCCUUA 1140 TAAGGCCA GGCTAGCTACAACGA CATGGCCT 2842 5152 CCAUGAUG G CCUUACAC 1141 GTGTAAGG GGCTAGCTACAACGA CATCATGG 2843

5157 AUGGCCUU A CACUGAAA 1142 TTTCAGTG GGCTAGCTACAACGA AAGGCCAT 2844

5159 GGCCUUAC A CUGAAAAU 1143 ATTTTCAG GGCTAGCTACAACGA GTAAGGCC 2845

5166 CACUGAAA A UGUCAGAU 1144 ATGTGACA GGCTAGCTACAACGA TTTCAGTG 2846

5168 CUGAAAAU G UCACAUUC 1145 GAATGTGA GGCTAGCTACAACGA ATTTTCAG 2847

5171 AAAAUGUC A CAUUCUAU 1146 ATAGAATG GGCTAGCTACAACGA GACATTTT 2848

5173 AAUGUCAC A UUCUAUUU 1147 AAATAGAA GGCTAGCTACAACGA GTGACATT 2849

5178 CACAUUCU A UUUUGGGU 1148 ACCCAAAA GGCTAGCTACAACGA AGAATGTG 2850

5185 UAUUUUGG G UAUUAAUA 1149 TATTAATA GGCTAGCTACAACGA CCAAAATA 2851

5187 UUUUGGGU A UUAAUAUA 1150 TATATTAA GGCTAGCTACAACGA ACCCAAAA 2852

5191 GGGUAUUA A UAUAUAGU 1151 ACTATATA GGCTAGCTACAACGA TAATACCC 2853

5193 GUAUUAAU A UAUAGUCC 1152 GGACTATA GGCTAGCTACAACGA ATTAATAC 2854

5195 AUUAAUAU A UAGUCCAG 1153 CTGGACTA GGCTAGCTACAACGA ATATTAAT 2855

5198 AAUAUAUA G UCCAGACA 1154 TGTCTGGA GGCTAGCTACAACGA TATATATT 2856

5204 UAGUCCAG A CACUUAAC 1155 GTTAAGTG GGCTAGCTACAACGA CTGGACTA 2857

5206 GUCCAGAC A CUUAACUC 1156 GAGTTAAG GGCTAGCTACAACGA GTCTGGAC 2858

5211 GACACUUA A CUCAAUUU 1157 AAATTGAG GGCTAGCTACAACGA TAAGTGTC 2859

5216 UUAACUCA A UUUCUUGG 1158 CCAAGAAA GGCTAGCTACAACGA TGAGTTAA 2860

5224 AUUUCUUG G UAUUAUUC 1159 GAATAATA GGCTAGCTACAACGA CAAGAAAT 2861

5226 UUCUUGGU A UUAUUCUG 1160 CAGAATAA GGCTAGCTACAACGA ACCAAGAA 2862

5229 UUGGUAUU A UUCUGUUU 1161 AAACAGAA GGCTAGCTACAACGA AATACCAA 2863

5234 AUUAUUCU G UUUUGCAC 1162 GTGCAAAA GGCTAGCTACAACGA AGAATAAT 2864

5239 UCUGUUUU G CACAGUUA 1163 TAACTGTG GGCTAGCTACAACGA AAAACAGA 2865

5241 UGUUUUGC A CAGUUAGU 1164 ACTAACTG GGCTAGCTACAACGA GCAAAACA 2866

5244 UUUGCACA G UUAGUUGU 1165 ACAACTAA GGCTAGCTACAACGA TGTGCAAA 2867

5248 CACAGUUA G UUGUGAAA 1166 TTTCACAA GGCTAGCTACAACGA TAACTGTG 2868

5251 AGUUAGUU G UGAAAGAA 1167 TTCTTTCA GGCTAGCTACAACGA AACTAACT 2869

5261 GAAAGAAA G CUGAGAAG 1168 CTTCTCAG GGCTAGCTACAACGA TTTCTTTC 2870

5271 UGAGAAGA A UGAAAAUG 1169 CATTTTCA GGCTAGCTACAACGA TCTTCTCA 2871

5277 GAAUGAAA A UGCAGUCC 1170 GGACTGCA GGCTAGCTACAACGA TTTCATTC 2872

5279 AUGAAAAU G CAGUCCUG 1171 CAGGACTG GGCTAGCTACAACGA ATTTTCAT 2873

5282 AAAAUGCA G UCCUGAGG 1172 CCTCAGGA GGCTAGCTACAACGA TGCATTTT 2874

5294 UGAGGAGA G UUUUCUCC 1173 GGAGAAAA GGCTAGCTACAACGA TCTCCTCA 2875

5303 UUUUCUCC A UAUCAAAA 1174 TTTTGATA GGCTAGCTACAACGA GGAGAAAA 2876

5305 UUCUCCAU A UCAAAACG 1175 CGTTTTGA GGCTAGCTACAACGA ATGGAGAA 2877

5311 AUAUCAAA A CGAGGGCU 1176 AGCCCTCG GGCTAGCTACAACGA TTTGATAT 2878

5317 AAACGAGG G CUGAUGGA 1177 TCCATCAG GGCTAGCTACAACGA CCTCGTTT 2879

5321 GAGGGCUG A UGGAGGAA 1178 TTCCTCCA GGCTAGCTACAACGA CAGCCCTC 2880

5334 GGAAAAAG G UCAAUAAG 1179 CTTATTGA GGCTAGCTACAACGA CTTTTTCC 2881

5338 AAAGGUCA A UAAGGUCA 1180 TGACCTTA GGCTAGCTACAACGA TGACCTTT 2882

5343 UCAAUAAG G UCAAGGGA 1181 TCCCTTGA GGCTAGCTACAACGA CTTATTGA 2883

5354 AAGGGAAG A CCCCGUCU 1182 AGACGGGG GGCTAGCTACAACGA CTTCCCTT 2884

5359 AAGACCCC G UCUCUAUA 1183 TATAGAGA GGCTAGCTACAACGA GGGGTCTT 2885

5365 CCGUCUCU A UACCAACC 1184 GGTTGGTA GGCTAGCTACAACGA AGAGACGG 2886

5367 GUCUCUAU A CCAACCAA 1185 TTGGTTGG GGCTAGCTACAACGA ATAGAGAC 2887

5371 CUAUACCA A CCAAACCA 1186 TGGTTTGG GGCTAGCTACAACGA TGGTATAG 2888

5376 CCAACCAA A CCAAUUCA 1187 TGAATTGG GGCTAGCTACAACGA TTGGTTGG 2889

5380 CCAAACCA A UUCACCAA 1188 TTGGTGAA GGCTAGCTACAACGA TGGTTTGG 2890

5384 ACCAAUUC A CCAACACA 1189 TGTGTTGG GGCTAGCTACAACGA GAATTGGT 2891

5388 AUUCACCA A CACAGUUG 1190 CAACTGTG GGCTAGCTACAACGA TGGTGAAT 2892

5390 UCACCAAC A CAGUUGGG 1191 CCCAACTG GGCTAGCTACAACGA GTTGGTGA 2893

5393 CCAACACA G UUGGGACC 1192 GGTCCCAA GGCTAGCTACAACGA TGTGTTGG 2894 5399 CAGUUGGG A CCCAAAAC 1193 GTTTTGGG GGCTAGCTACAACGA CCCAACTG 2895

5406 GACCCAAA A CACAGGAA 1194 TTCCTGTG GGCTAGCTACAACGA TTTGGGTC 2896

5408 CCCAAAAC A CAGGAAGU 1195 ACTTCCTG GGCTAGCTACAACGA GTTTTGGG 2897

5415 GACAGGAA G UCAGUCAC 1196 GTGACTGA GGCTAGCTACAACGA TTCCTGTG 2898

5419 GGAAGUCA G UCACGUUU 1197 AAACGTGA GGCTAGCTACAACGA TGACTTCC 2899

5422 AGUCAGUC A CGUUUCCU 1198 AGGAAACG GGCTAGCTACAACGA GACTGACT 2900

5424 UCAGUCAC G UUUCCUUU 1199 AAAGGAAA GGCTAGCTACAACGA GTGACTGA 2901

5435 UCCUUUUC A UUUAAUGG 1200 CCATTAAA GGCTAGCTACAACGA GAAAAGGA 2902

5440 UUCAUUUA A UGGGGAUU 1201 AATCCCCA GGCTAGCTACAACGA TAAATGAA 2903

5446 UAAUGGGG A UUCCACUA 1202 TAGTGGAA GGCTAGCTACAACGA CCCCATTA 2904

5451 GGGAUUCC A CUAUCUCA 1203 TGAGATAG GGCTAGCTACAACGA GGAATCCC 2905

5454 AUUCCACU A UCUCACAC 1204 GTGTGAGA GGCTAGCTACAACGA AGTGGAAT 2906

5459 ACUAUCUC A CACUAAUC 1205 GATTAGTG GGCTAGCTACAACGA GAGATAGT 2907

5461 UAUCUCAC A CUAAUCUG 1206 CAGATTAG GGCTAGCTACAACGA GTGAGATA 2908

5465 UCACACUA A UCUGAAAG 1207 CTTTCAGA GGCTAGCTACAACGA TAGTGTGA 2909

5475 CUGAAAGG A UGUGGAAG 1208 CTTCCACA GGCTAGCTACAACGA CCTTTCAG 2910

5477 GAAAGGAU G UGGAAGAG 1209 CTCTTCCA GGCTAGCTACAACGA ATCCTTTC 2911

5485 GUGGAAGA G CAUUAGCU 1210 AGCTAATG GGCTAGCTACAACGA TCTTCCAC 2912

5487 GGAAGAGC A UUAGCUGG 1211 CCAGCTAA GGCTAGCTACAACGA GCTCTTCC 2913

5491 GAGCAUUA G CUGGCGCA 1212 TGCGCCAG GGCTAGCTACAACGA TAATGCTC 2914

5495 AUUAGCUG G CGCAUAUU 1213 AATATGCG GGCTAGCTACAACGA CAGCTAAT 2915

5497 UAGCUGGC G CAUAUUAA 1214 TTAATATG GGCTAGCTACAACGA GCCAGCTA 2916

5499 GCUGGCGC A UAUUAAGC 1215 GCTTAATA GGCTAGCTACAACGA GCGCCAGC 2917

5501 UGGCGCAU A UUAAGCAC 1216 GTGCTTAA GGCTAGCTACAACGA ATGCGCCA 2918

5506 CAUAUUAA G CACUUUAA 1217 TTAAAGTG GGCTAGCTACAACGA TTAATATG 2919

5508 UAUUAAGC A CUUUAAGC 1218 GCTTAAAG GGCTAGCTACAACGA GCTTAATA 2920

5515 CACUUUAA G CUCCUUGA 1219 TCAAGGAG GGCTAGCTACAACGA TTAAAGTG 2921

5524 CUCCUUGA G UAAAAAGG 1220 CCTTTTTA GGCTAGCTACAACGA TCAAGGAG 2922

5532 GUAAAAAG G UGGUAUGU 1221 ACATACCA GGCTAGCTACAACGA CTTTTTAC 2923

5535 AAAAGGUG G UAUGUAAU 1222 ATTACATA GGCTAGCTACAACGA CACCTTTT 2924

5537 AAGGUGGU A UGUAAUUU 1223 AAATTACA GGCTAGCTACAACGA ACCACCTT 2925

5539 GGUGGUAU G UAAUUUAU 1224 ATAAATTA GGCTAGCTACAACGA ATACCACC 2926

5542 GGUAUGUA A UUUAUGCA 1225 TGCATAAA GGCTAGCTACAACGA TACATACC 2927

5546 UGUAAUUU A UGCAAGGU 1226 ACGTTGCA GGCTAGCTACAACGA AAATTACA 2928

5548 UAAUUUAU G CAAGGUAU 1227 ATACCTTG GGCTAGCTACAACGA ATAAATTA 2929

5553 UAUGCAAG G UAUUUCUC 1228 GAGAAATA GGCTAGCTACAACGA CTTGCATA 2930

5555 UGCAAGGU A UUUCUCCA 1229 TGGAGAAA GGCTAGCTACAACGA ACCTTGCA 2931

5564 UUUCUCCA G UUGGGACU 1230 AGTCCCAA GGCTAGCTACAACGA TGGAGAAA 2932

5570 CAGUUGGG A CUCAGGAU 1231 ATCCTGAG GGCTAGCTACAACGA CCCAACTG 2933

5577 GACUCAGG A UAUUAGUU 1232 AACTAATA GGCTAGCTACAACGA CCTGAGTC 2934

5579 CUCAGGAU A UUAGUUAA 1233 TTAACTAA GGCTAGCTACAACGA ATCCTGAG 2935

5583 GGAUAUUA G UUAAUGAG 1234 CTCATTAA GGCTAGCTACAACGA TAATATCC 2936

5587 AUUAGUUA A UGAGCCAU 1235 ATGGCTCA GGCTAGCTACAACGA TAACTAAT 2937

5591 GUUAAUGA G CCAUCACU 1236 AGTGATGG GGCTAGCTACAACGA TCATTAAC 2938

5594 AAUGAGCC A UCACUAGA 1237 TCTAGTGA GGCTAGCTACAACGA GGCTCATT 2939

5597 GAGCCAUC A CUAGAAGA 1238 TCTTCTAG GGCTAGCTACAACGA GATGGCTC 2940

5609 GAAGAAAA G CCCAUUUU 1239 AAAATGGG GGCTAGCTACAACGA TTTTCTTC 2941

5613 AAAAGCCC A UUUUCAAC 1240 GTTGAAAA GGCTAGCTACAACGA GGGCTTTT 2942

5620 CAUUUUCA A CUGCUUUG 1241 CAAAGCAG GGCTAGCTACAACGA TGAAAATG 2943

5623 UUUCAACU G CUUUGAAA 1242 TTTCAAAG GGCTAGCTACAACGA AGTTGAAA 2944

5631 GCUUUGAA A CUUGCCUG 1243 CAGGCAAG GGCTAGCTACAACGA TTCAAAGC 2945

5635 UGAAACUU G CCUGGGGU 1244 ACCCCAGG GGCTAGCTACAACGA AAGTTTCA 2946 5642 UGCCUGGG G UCUGAGCA 1245 TGCTCAGA GGCTAGCTACAACGA CCCAGGCA 2947

5648 GGGUCUGA G CAUGAUGG 1246 CCATCATG GGCTAGCTACAACGA TCAGACCC 2948

5650 GUCUGAGC A UGAUGGGA 1247 TCCCATCA GGCTAGCTACAACGA GCTCAGAC 2949

5653 UGAGCAUG A UGGGAAUA 1248 TATTCCCA GGCTAGCTACAACGA CATGCTCA 2950

5659 UGAUGGGA A UAGGGAGA 1249 TCTCCCTA GGCTAGCTACAACGA TCCCATCA 2951

5667 AUAGGGAG A CAGGGUAG 1250 CTACCCTG GGCTAGCTACAACGA CTCCCTAT 2952

5672 GAGACAGG G UAGGAAAG 1251 CTTTCCTA GGCTAGCTACAACGA CCTGTCTC 2953

5682 AGGAAAGG G CGCCUACU 1252 AGTAGGCG GGCTAGCTACAACGA CCTTTCCT 2954

5684 GAAAGGGC G CCUACUCU 1253 AGAGTAGG GGCTAGCTACAACGA GCCCTTTC 2955

5688 GGGCGCCU A CUCUUCAG 1254 CTGAAGAG GGCTAGCTACAACGA AGGCGCCC 2956

5698 UCUUCAGG G UCUAAAGA 1255 TCTTTAGA GGCTAGCTACAACGA CCTGAAGA 2957

5706 GUCUAAAG A UCAAGUGG 1256 CCACTTGA GGCTAGCTACAACGA CTTTAGAC 2958

5711 AAGAUCAA G UGGGCCUU 1257 AAGGCCCA GGCTAGCTACAACGA TTGATCTT 2959

5715 UCAAGUGG G CCUUGGAU 1258 ATCCAAGG GGCTAGCTACAACGA CCACTTGA 2960

5722 GGCCUUGG A UCGCUAAG 1259 CTTAGCGA GGCTAGCTACAACGA CCAAGGCC 2961

5725 CUUGGAUC G CUAAGCUG 1260 CAGCTTAG GGCTAGCTACAACGA GATCCAAG 2962

5730 AUCGCUAA G CUGGCUCU 1261 AGAGCCAG GGCTAGCTACAACGA TTAGCGAT 2963

5734 CUAAGCUG G CUCUGUUU 1262 AAACAGAG GGCTAGCTACAACGA CAGCTTAG 2964

5739 CUGGCUCU G UUUGAUGC 1263 GCATCAAA GGCTAGCTACAACGA AGAGCCAG 2965

5744 UCUGUUUG A UGCUAUUU 1264 AAATAGCA GGCTAGCTACAACGA CAAACAGA 2966

5746 UGUUUGAU G CUAUUUAU 1265 ATAAATAG GGCTAGCTACAACGA ATCAAACA 2967

5749 UUGAUGCU A UUUAUGCA 1266 TGCATAAA GGCTAGCTACAACGA AGCATCAA 2968

5753 UGCUAUUU A UGCAAGUU 1267 AACTTGCA GGCTAGCTACAACGA AAATAGCA 2969

5755 CUAUUUAU G CAAGUUAG 1268 CTAACTTG GGCTAGCTACAACGA ATAAATAG 2970

5759 UUAUGCAA G UUAGGGUC 1269 GACCCTAA GGCTAGCTACAACGA TTGCATAA 2971

5765 AAGUUAGG G UCUAUGUA 1270 TACATAGA GGCTAGCTACAACGA CCTAACTT 2972

5769 UAGGGUCU A UGUAUUUA 1271 TAAATACA GGCTAGCTACAACGA AGACCCTA 2973

5771 GGGUCUAU G UAUUUAGG 1272 CCTAAATA GGCTAGCTACAACGA ATAGACCC 2974

5773 GUCUAUGU A UUUAGGAU 1273 ATCCTAAA GGCTAGCTACAACGA ACATAGAC 2975

5780 UAUUUAGG A UGCGCCUA 1274 TAGGCGCA GGCTAGCTACAACGA CCTAAATA 2976

5782 UUUAGGAU G CGCCUACU 1275 AGTAGGCG GGCTAGCTACAACGA ATCCTAAA 2977

5784 UAGGAUGC G CCUACUCU 1276 AGAGTAGG GGCTAGCTACAACGA GCATCCTA 2978

5788 AUGCGCCU A CUCUUCAG 1277 CTGAAGAG GGCTAGCTACAACGA AGGCGCAT 2979

5798 UCUUCAGG G UCUAAAGA 1278 TCTTTAGA GGCTAGCTACAACGA CCTGAAGA 2980

5806 GUCUAAAG A UCAAGUGG 1279 CCACTTGA GGCTAGCTACAACGA CTTTAGAC 2981

5811 AAGAUCAA G UGGGCCUU 1280 AAGGCCCA GGCTAGCTACAACGA TTGATCTT 2982

5815 UCAAGUGG G CCUUGGAU 1281 ATCCAAGG GGCTAGCTACAACGA CCACTTGA 2983

5822 GGCCUUGG A UCGCUAAG 1282 CTTAGCGA GGCTAGCTACAACGA CCAAGGCC 2984

5825 CUUGGAUC G CUAAGCUG 1283 CAGCTTAG GGCTAGCTACAACGA GATCCAAG 2985

5830 AUCGCUAA G CUGGCUCU 1284 AGAGCCAG GGCTAGCTACAACGA TTAGCGAT 2986

5834 CUAAGCUG G CUCUGUUU 1285 AAACAGAG GGCTAGCTACAACGA CAGCTTAG 2987

5839 CUGGCUCU G UUUGAUGC 1286 GCATCAAA GGCTAGCTACAACGA AGAGCCAG 2988

5844 UCUGUUUG A UGCUAUUU 1287 AAATAGCA GGCTAGCTACAACGA CAAACAGA 2989

5846 UGUUUGAU G CUAUUUAU 1288 ATAAATAG GGCTAGCTACAACGA ATCAAACA 2990

5849 UUGAUGCU A UUUAUGCA 1289 TGCATAAA GGCTAGCTACAACGA AGCATCAA 2991

5853 UGCUAUUU A UGCAAGUU 1290 AACTTGCA GGCTAGCTACAACGA AAATAGCA 2992

5855 CUAUUUAU G CAAGUUAG 1291 CTAACTTG GGCTAGCTACAACGA ATAAATAG 2993

5859 UUAUGCAA G UUAGGGUC 1292 GACCCTAA GGCTAGCTACAACGA TTGCATAA 2994

5865 AAGUUAGG G UCUAUGUA 1293 TACATAGA GGCTAGCTACAACGA CCTAACTT 2995

5869 UAGGGUCU A UGUAUUUA 1294 TAAATACA GGCTAGCTACAACGA AGACCCTA 2996

5871 GGGUCUAU G UAUUUAGG 1295 CCTAAATA GGCTAGCTACAACGA ATAGACCC 2997

5873 GUCUAUGU A UUUAGGAU 1296 ATCCTAAA GGCTAGCTACAACGA ACATAGAC 2998 5880 UAUUUAGG A UGUCUGCA 1297 TGCAGACA GGCTAGCTACAACGA CCTAAATA 2999

5882 UUUAGGAU G UCUGCACC 1298 GGTGCAGA GGCTAGCTACAACGA ATCCTAAA 3000

5886 GGAUGUCU G CACCUUCU 1299 AGAAGGTG GGCTAGCTACAACGA AGACATCC 3001

5888 AUGUCUGC A CCUUCUGC 1300 GCAGAAGG GGCTAGCTACAACGA GCAGACAT 3002

5895 CACCUUCU G CAGCCAGU 1301 ACTGGCTG GGCTAGCTACAACGA AGAAGGTG 3003

5898 CUUCUGCA G CCAGUCAG 1302 CTGACTGG GGCTAGCTACAACGA TGCAGAAG 3004

5902 UGCAGCCA G UCAGAAGC 1303 GCTTCTGA GGCTAGCTACAACGA TGGCTGCA 3005

5909 AGUCAGAA G CUGGAGAG 1304 CTCTCCAG GGCTAGCTACAACGA TTCTGACT 3006

5918 CUGGAGAG G CAACAGUG 1305 CACTGTTG GGCTAGCTACAACGA CTCTCCAG 3007

5921 GAGAGGCA A CAGUGGAU 1306 ATCCACTG GGCTAGCTACAACGA TGCCTCTC 3008

5924 AGGCAACA G UGGAUUGC 1307 GCAATCCA GGCTAGCTACAACGA TGTTGCCT 3009

5928 AACAGUGG A UUGCUGCU 1308 AGCAGCAA GGCTAGCTACAACGA CCACTGTT 3010

5931 AGUGGAUU G CUGCUUCU 1309 AGAAGCAG GGCTAGCTACAACGA AATCCACT 3011

5934 GGAUUGCU G CUUCUUGG 1310 CCAAGAAG GGCTAGCTACAACGA AGCAATCC 3012

5951 GGAGAAGA G UAUGCUUC 1311 GAAGCATA GGCTAGCTACAACGA TCTTCTCC 3013

5953 AGAAGAGU A UGCUUCCU 1312 AGGAAGCA GGCTAGCTACAACGA ACTCTTCT 3014

5955 AAGAGUAU G CUUCCUUU 1313 AAAGGAAG GGCTAGCTACAACGA ATACTCTT 3015

5965 UUCCUUUU A UCCAUGUA 1314 TACATGGA GGCTAGCTACAACGA AAAAGGAA 3016

5969 UUUUAUCC A UGUAAUUU 1315 AAATTACA GGCTAGCTACAACGA GGATAAAA 3017

5971 UUAUCCAU G UAAUUUAA 1316 TTAAATTA GGCTAGCTACAACGA ATGGATAA 3018

5974 UCCAUGUA A UUUAACUG 1317 CAGTTAAA GGCTAGCTACAACGA TACATGGA 3019

5979 GUAAUUUA A CUGUAGAA 1318 TTCTACAG GGCTAGCTACAACGA TAAATTAC 3020

5982 AUUUAACU G UAGAACCU 1319 AGGTTCTA GGCTAGCTACAACGA AGTTAAAT 3021

5987 ACUGUAGA A CCUGAGCU 1320 AGCTCAGG GGCTAGCTACAACGA TCTACAGT 3022

5993 GAACCUGA G CUCUAAGU 1321 ACTTAGAG GGCTAGCTACAACGA TCAGGTTC 3023

6000 AGCUCUAA G UAACCGAA 1322 TTCGGTTA GGCTAGCTACAACGA TTAGAGCT 3024

6003 UCUAAGUA A CCGAAGAA 1323 TTCTTCGG GGCTAGCTACAACGA TACTTAGA 3025

6011 ACCGAAGA A UGUAUGCC 1324 GGCATACA GGCTAGCTACAACGA TCTTCGGT 3026

6013 CGAAGAAU G UAUGCCUC 1325 GAGGCATA GGCTAGCTACAACGA ATTCTTCG 3027

6015 AAGAAUGU A UGCCUCUG 1326 CAGAGGCA GGCTAGCTACAACGA ACATTCTT 3028

6017 GAAUGUAU G CCUCUGUU 1327 AACAGAGG GGCTAGCTACAACGA ATACATTC 3029

6023 AUGCCUCU G UUCUUAUG 1328 CATAAGAA GGCTAGCTACAACGA AGAGGCAT 3030

6029 CUGUUCUU A UGUGCCAC 1329 GTGGCACA GGCTAGCTACAACGA AAGAACAG 3031

6031 GUUCUUAU G UGCCACAU 1330 ATGTGGCA GGCTAGCTACAACGA ATAAGAAC 3032

6033 UCUUAUGU G CCACAUCC 1331 GGATGTGG GGCTAGCTACAACGA ACATAAGA 3033

6036 UAUGUGCC A CAUCCUUG 1332 CAAGGATG GGCTAGCTACAACGA GGCACATA 3034

6038 UGUGCCAC A UCCUUGUU 1333 AACAAGGA GGCTAGCTACAACGA GTGGCACA 3035

6044 ACAUCCUU G UUUAAAGG 1334 CCTTTAAA GGCTAGCTACAACGA AAGGATGT 3036

6052 GUUUAAAG G CUCUCUGU 1335 ACAGAGAG GGCTAGCTACAACGA CTTTAAAC 3037

6059 GGCUCUCU G UAUGAAGA 1336 TCTTCATA GGCTAGCTACAACGA AGAGAGCC 3038

6061 CUCUCUGU A UGAAGAGA 1337 TCTCTTCA GGCTAGCTACAACGA ACAGAGAG 3039

6069 AUGAAGAG A UGGGACCG 1338 CGGTCCCA GGCTAGCTACAACGA CTCTTCAT 3040

6074 GAGAUGGG A CCGUCAUC 1339 GATGACGG GGCTAGCTACAACGA CCCATCTC 3041

6077 AUGGGACC G UCAUCAGC 1340 GCTGATGA GGCTAGCTACAACGA GGTCCCAT 3042

6080 GGACCGUC A UCAGCACA 1341 TGTGCTGA GGCTAGCTACAACGA GACGGTCC 3043

6084 CGUCAUCA G CACAUUCC 1342 GGAATGTG GGCTAGCTACAACGA TGATGACG 3044

6086 UCAUCAGC A CAUUCCCU 1343 AGGGAATG GGCTAGCTACAACGA GCTGATGA 3045

6088 AUCAGCAC A UUCCCUAG 1344 CTAGGGAA GGCTAGCTACAACGA GTGCTGAT 3046

6096 AUUCCCUA G UGAGCCUA 1345 TAGGCTCA GGCTAGCTACAACGA TAGGGAAT 3047

6100 CCUAGUGA G CCUACUGG 1346 CCAGTAGG GGCTAGCTACAACGA TCACTAGG 3048

6104 GUGAGCCU A CUGGCUCC 1347 GGAGCCAG GGCTAGCTACAACGA AGGCTCAC 3049

6108 GCCUACUG G CUCCUGGC 1348 GCCAGGAG GGCTAGCTACAACGA CAGTAGGC 3050 6115 GGCUCCUG G CAGCGGCU 1349 AGCCGCTG GGCTAGCTACAACGA CAGGAGCC 3051

6118 UCCUGGCA G CGGCUUUU 1350 AAAAGCCG GGCTAGCTACAACGA TGCCAGGA 3052

6121 UGGCAGCG G CUUUUGUG 1351 CACAAAAG GGCTAGCTACAACGA CGCTGCCA 3053

6127 CGGCUUUU G UGGAAGAC 1352 GTCTTCCA GGCTAGCTACAACGA AAAAGCCG 3054

6134 UGUGGAAG A CUCACUAG 1353 CTAGTGAG GGCTAGCTACAACGA CTTCCACA 3055

6138 GAAGACUC A CUAGCCAG 1354 CTGGCTAG GGCTAGCTACAACGA GAGTCTTC 3056

6142 ACUCACUA G CCAGAAGA 1355 TCTTCTGG GGCTAGCTACAACGA TAGTGAGT 3057

6156 AGAGAGGA G UGGGACAG 1356 CTGTCCCA GGCTAGCTACAACGA TCCTCTCT 3058

6161 GGAGUGGG A CAGUCCUC 1357 GAGGACTG GGCTAGCTACAACGA CCCACTCC 3059

6164 GUGGGACA G UCCUCUCC 1358 GGAGAGGA GGCTAGCTACAACGA TGTCCCAC 3060

6173 UCCUCUCC A CCAAGAUC 1359 GATCTTGG GGCTAGCTACAACGA GGAGAGGA 3061

6179 CCACCAAG A UCUAAAUC 1360 GATTTAGA GGCTAGCTACAACGA CTTGGTGG 3062

6185 AGAUCUAA A UCCAAACA 1361 TGTTTGGA GGCTAGCTACAACGA TTAGATCT 3063

6191 AAAUCCAA A CAAAAGCA 1362 TGCTTTTG GGCTAGCTACAACGA TTGGATTT 3064

6197 AAACAAAA G CAGGCUAG 1363 CTAGCCTG GGCTAGCTACAACGA TTTTGTTT 3065

6201 AAAAGCAG G CUAGAGCC 1364 GGCTCTAG GGCTAGCTACAACGA CTGCTTTT 3066

6207 AGGCUAGA G CCAGAAGA 1365 TCTTCTGG GGCTAGCTACAACGA TCTAGCCT 3067

6220 AAGAGAGG A CAAAUCUU 1366 AAGATTTG GGCTAGCTACAACGA CCTCTCTT 3068

6224 GAGGACAA A UCUUUGUU 1367 AACAAAGA GGCTAGCTACAACGA TTGTCCTC 3069

6230 AAAUCUUU G UUGUUCCU 1368 AGGAACAA GGCTAGCTACAACGA AAAGATTT 3070

6233 UCUUUGUU G UUCCUCUU 1369 AAGAGGAA GGCTAGCTACAACGA AACAAAGA 3071

6246 UCUUCUUU A CACAUACG 1370 CGTATGTG GGCTAGCTACAACGA AAAGAAGA 3072

6248 UUCUUUAC A CAUACGCA 1371 TGCGTATG GGCTAGCTACAACGA GTAAAGAA 3073

6250 CUUUACAC A UACGCAAA 1372 TTTGCGTA GGCTAGCTACAACGA GTGTAAAG 3074

6252 UUACACAU A CGCAAACC 1373 GGTTTGCG GGCTAGCTACAACGA ATGTGTAA 3075

6254 ACACAUAC G CAAACCAC 1374 GTGGTTTG GGCTAGCTACAACGA GTATGTGT 3076

6258 AUACGCAA A CCACCUGU 1375 ACAGGTGG GGCTAGCTACAACGA TTGCGTAT 3077

6261 CGCAAACC A CCUGUGAC 1376 GTCACAGG GGCTAGCTACAACGA GGTTTGCG 3078

6265 AACCACCU G UGACAGCU 1377 AGCTGTCA GGCTAGCTACAACGA AGGTGGTT 3079

6268 CACCUGUG A CAGCUGGC 1378 GCCAGCTG GGCTAGCTACAACGA CACAGGTG 3080

6271 CUGUGACA G CUGGCAAU 1379 ATTGCCAG GGCTAGCTACAACGA TGTCACAG 3081

6275 GACAGCUG G CAAUUUUA 1380 TAAAATTG GGCTAGCTACAACGA CAGCTGTC 3082

6278 AGCUGGCA A UUUUAUAA 1381 TTATAAAA GGCTAGCTACAACGA TGCCAGCT 3083

6283 GCAAUUUU A UAAAUCAG 1382 CTGATTTA GGCTAGCTACAACGA AAAATTGC 3084

6287 UUUUAUAA A UCAGGUAA 1383 TTACCTGA GGCTAGCTACAACGA TTATAAAA 3085

6292 UAAAUCAG G UAACUGGA 1384 TCCAGTTA GGCTAGCTACAACGA CTGATTTA 3086

6295 AUCAGGUA A CUGGAAGG 1385 CCTTCCAG GGCTAGCTACAACGA TACCTGAT 3087

6306 GGAAGGAG G UUAAACUC 1386 GAGTTTAA GGCTAGCTACAACGA CTCCTTCC 3088

6311 GAGGUUAA A CUCAGAAA 1387 TTTCTGAG GGCTAGCTACAACGA TTAACCTC 3089

6327 AAAAGAAG A CCUCAGUG 1388 GACTGAGG GGCTAGCTACAACGA CTTCTTTT 3090

6333 AGACCUCA G UCAAUUCU 1389 AGAATTGA GGCTAGCTACAACGA TGAGGTCT 3091

6337 CUCAGUCA A UUCUCUAC 1390 GTAGAGAA GGCTAGCTACAACGA TGACTGAG 3092

6344 AAUUCUCU A CUUUUUUU 1391 AAAAAAAG GGCTAGCTACAACGA AGAGAATT 3093

6366 UUUUCCAA A UCAGAUAA 1392 TTATCTGA GGCTAGCTACAACGA TTGGAAAA 3094

6371 CAAAUCAG A UAAUAGCC 1393 GGCTATTA GGCTAGCTACAACGA CTGATTTG 3095

6374 AUCAGAUA A UAGCCCAG 1394 CTGGGCTA GGCTAGCTACAACGA TATCTGAT 3096

6377 AGAUAAUA G CCCAGCAA 1395 TTGCTGGG GGCTAGCTACAACGA TATTATCT 3097

6382 AUAGCCCA G CAAAUAGU 1396 ACTATTTG GGCTAGCTACAACGA TGGGCTAT 3098

6386 CCCAGCAA A UAGUGAUA 1397 TATCACTA GGCTAGCTACAACGA TTGCTGGG 3099

6389 AGCAAAUA G UGAUAACA 1398 TGTTATCA GGCTAGCTACAACGA TATTTGCT 3100

6392 AAAUAGUG A UAACAAAU 1399 ATTTGTTA GGCTAGCTACAACGA CACTATTT 3101

6395 UAGUGAUA A CAAAUAAA 1400 TTTATTTG GGCTAGCTACAACGA TATCACTA 3102 6399 GAUAACAA A UAAAACCU 1401 AGGTTTTA GGCTAGCTACAACGA TTGTTATC 3103

6404 CAAAUAAA A CCUUAGCU 1402 AGCTAAGG GGCTAGCTACAACGA TTTATTTG 3104

6410 AAACCUUA G CUGUUCAU 1403 ATGAACAG GGCTAGCTACAACGA TAAGGTTT 3105

6413 CCUUAGCU G UUCAUGUC 1404 GACATGAA GGCTAGCTACAACGA AGCTAAGG 3106

6417 AGCUGUUC A UGUCUUGA 1405 TCAAGACA GGCTAGCTACAACGA GAACAGCT 3107

6419 CUGUUCAU G UCUUGAUU 1406 AATCAAGA GGCTAGCTACAACGA ATGAACAG 3108

6425 AUGUCUUG A UUUCAAUA 1407 TATTGAAA GGCTAGCTACAACGA CAAGACAT 3109

6431 UGAUUUCA A UAAUUAAU 1408 ATTAATTA GGCTAGCTACAACGA TGAAATCA 3110

6434 UUUCAAUA A UUAAUUCU 1409 AGAATTAA GGCTAGCTACAACGA TATTGAAA 3111

6438 AAUAAUUA A UUCUUAAU 1410 ATTAAGAA GGCTAGCTACAACGA TAATTATT 3112

6445 AAUUCUUA A UCAUUAAG 1411 CTTAATGA GGCTAGCTACAACGA TAAGAATT 3113

6448 UCUUAAUC A UUAAGAGA 1412 TCTCTTAA GGCTAGCTACAACGA GATTAAGA 3114

6456 AUUAAGAG A CCAUAAUA 1413 TATTATGG GGCTAGCTACAACGA CTCTTAAT 3115

6459 AAGAGACC A UAAUAAAU 1414 ATTTATTA GGCTAGCTACAACGA GGTCTCTT 3116

6462 AGACCAUA A UAAAUACU 1415 AGTATTTA GGCTAGCTACAACGA TATGGTCT 3117

6466 CAUAAUAA A UACUCCUU 1416 AAGGAGTA GGCTAGCTACAACGA TTATTATG 3118

6468 UAAUAAAU A CUCCUUUU 1417 AAAAGGAG GGCTAGCTACAACGA ATTTATTA 3119

6487 AGAGAAAA G CAAAACCA 1418 TGGTTTTG GGCTAGCTACAACGA TTTTCTCT 3120

6492 AAAGGAAA A CCAUUAGA 1419 TCTAATGG GGCTAGCTACAACGA TTTGCTTT 3121

6495 GCAAAACC A UUAGAAUU 1420 AATTCTAA GGCTAGCTACAACGA GGTTTTGC 3122

6501 CCAUUAGA A UUGUUACU 1421 AGTAACAA GGCTAGCTACAACGA TCTAATGG 3123

6504 UUAGAAUU G UUACUCAG 1422 CTGAGTAA GGCTAGCTACAACGA AATTCTAA 3124

6507 GAAUUGUU A CUCAGCUC 1423 GAGCTGAG GGCTAGCTACAACGA AACAATTC 3125

6512 GUUACUCA G CUCCUUGA 1424 TGAAGGAG GGCTAGCTACAACGA TGAGTAAC 3126

6522 UCCUUCAA A CUCAGGUU 1425 AACCTGAG GGCTAGCTACAACGA TTGAAGGA 3127

6528 AAACUCAG G UUUGUAGC 1426 GCTACAAA GGCTAGCTACAACGA CTGAGTTT 3128

6532 UCAGGUUU G UAGCAUAC 1427 GTATGCTA GGCTAGCTACAACGA AAACCTGA 3129

6535 GGUUUGUA G CAUACAUG 1428 CATGTATG GGCTAGCTACAACGA TACAAACC 3130

6537 UUUGUAGC A UACAUGAG 1429 CTCATGTA GGCTAGCTACAACGA GCTACAAA 3131

6539 UGUAGCAU A CAUGAGUC 1430 GACTCATG GGCTAGCTACAACGA ATGCTACA 3132

6541 UAGCAUAC A UGAGUCCA 1431 TGGACTCA GGCTAGCTACAACGA GTATGCTA 3133

6545 AUACAUGA G UCCAUCCA 1432 TGGATGGA GGCTAGCTACAACGA TCATGTAT 3134

6549 AUGAGUCC A UCCAUCAG 1433 CTGATGGA GGCTAGCTACAACGA GGACTCAT 3135

6553 GUCCAUCC A UCAGUCAA 1434 TTGACTGA GGCTAGCTACAACGA GGATGGAC 3136

6557 AUCCAUCA G UCAAAGAA 1435 TTCTTTGA GGCTAGCTACAACGA TGATGGAT 3137

6565 GUCAAAGA A UGGUUCCA 1436 TGGAACCA GGCTAGCTACAACGA TCTTTGAC 3138

6568 AAAGAAUG G UUCCAUCU 1437 AGATGGAA GGCTAGCTACAACGA CATTCTTT 3139

6573 AUGGUUCC A UCUGGAGU 1438 ACTCCAGA GGCTAGCTACAACGA GGAACCAT 3140

6580 CAUCUGGA G UCUUAAUG 1439 CATTAAGA GGCTAGCTACAACGA TCCAGATG 3141

6586 GAGUCUUA A UGUAGAAA 1440 TTTCTACA GGCTAGCTACAACGA TAAGACTC 3142

6588 GUCUUAAU G UAGAAAGA 1441 TCTTTCTA GGCTAGCTACAACGA ATTAAGAC 3143

6600 AAAGAAAA A UGGAGACU 1442 AGTCTCCA GGCTAGCTACAACGA TTTTCTTT 3144

6606 AAAUGGAG A CUUGUAAU 1443 ATTACAAG GGCTAGCTACAACGA CTCCATTT 3145

6610 GGAGACUU G UAAUAAUG 1444 CATTATTA GGCTAGCTACAACGA AAGTCTCC 3146

6613 GACUUGUA A UAAUGAGC 1445 GCTCATTA GGCTAGCTACAACGA TACAAGTC 3147

6616 UUGUAAUA A UGAGCUAG 1446 CTAGCTCA GGCTAGCTACAACGA TATTACAA 3148

6620 AAUAAUGA G CUAGUUAC 1447 GTAACTAG GGCTAGCTACAACGA TCATTATT 3149

6624 AUGAGCUA G UUACAAAG 1448 CTTTGTAA GGCTAGCTACAACGA TAGCTCAT 3150

6627 AGCUAGUU A CAAAGUGC 1449 GCACTTTG GGCTAGCTACAACGA AACTAGCT 3151

6632 GUUACAAA G UGCUUGUU 1450 AACAAGCA GGCTAGCTACAACGA TTTGTAAC 3152

6634 UACAAAGU G CUUGUUCA 1451 TGAACAAG GGCTAGCTACAACGA ACTTTGTA 3153

6638 AAGUGCUU G UUCAUUAA 1452 TTAATGAA GGCTAGCTACAACGA AAGCACTT 3154 6642 GCUUGUUC A UUAAAAUA 1453 TATTTTAA GGCTAGCTACAACGA GAACAAGC 3155

6648 UCAUUAAA A UAGCACUG 1454 CAGTGCTA GGCTAGCTACAACGA TTTAATGA 3156

6651 UUAAAAUA G CACUGAAA 1455 TTTCAGTG GGCTAGCTACAACGA TATTTTAA 3157

6653 AAAAUAGC A CUGAAAAU 1456 ATTTTCAG GGCTAGCTACAACGA GCTATTTT 3158

6660 CACUGAAA A UUGAAAGA 1457 TGTTTCAA GGCTAGCTACAACGA TTTCAGTG 3159

6666 AAAUUGAA A CAUGAAUU 1458 AATTCATG GGCTAGCTACAACGA TTCAATTT 3160

6668 AUUGAAAC A UGAAUUAA 1459 TTAATTCA GGCTAGCTACAACGA GTTTCAAT 3161

6672 AAACAUGA A UUAACUGA 1460 TCAGTTAA GGCTAGCTACAACGA TCATGTTT 3162

6676 AUGAAUUA A CUGAUAAU 1461 ATTATCAG GGCTAGCTACAACGA TAATTCAT 3163

6680 AUUAACUG A UAAUAUUC 1462 GAATATTA GGCTAGCTACAACGA CAGTTAAT 3164

6683 AACUGAUA A UAUUCCAA 1463 TTGGAATA GGCTAGCTACAACGA TATCAGTT 3165

6685 CUGAUAAU A UUCCAAUC 1464 GATTGGAA GGCTAGCTACAACGA ATTATCAG 3166

6691 AUAUUCCA A UCAUUUGC 1465 GCAAATGA GGCTAGCTACAACGA TGGAATAT 3167

6694 UUCCAAUC A UUUGCCAU 1466 ATGGCAAA GGCTAGCTACAACGA GATTGGAA 3168

6698 AAUCAUUU G CCAUUUAU 1467 ATAAATGG GGCTAGCTACAACGA AAATGATT 3169

6701 CAUUUGGC A UUUAUGAC 1468 GTCATAAA GGCTAGCTACAACGA GGCAAATG 3170

6705 UGCCAUUU A UGACAAAA 1469 TTTTGTCA GGCTAGCTACAACGA AAATGGCA 3171

6708 CAUUUAUG A CAAAAAUG 1470 CATTTTTG GGCTAGCTACAACGA CATAAATG 3172

6714 UGACAAAA A UGGUUGGC 1471 GCCAACCA GGCTAGCTACAACGA TTTTGTCA 3173

6717 CAAAAAUG G UUGGCACU 1472 AGTGCCAA GGCTAGCTACAACGA CATTTTTG 3174

6721 AAUGGUUG G CACUAACA 1473 TGTTAGTG GGCTAGCTACAACGA CAACCATT 3175

6723 UGGUUGGC A CUAACAAA 1474 TTTGTTAG GGCTAGCTACAACGA GCCAACCA 3176

6727 UGGCACUA A CAAAGAAC 1475 GTTCTTTG GGCTAGCTACAACGA TAGTGCCA 3177

6734 AACAAAGA A CGAGCACU 1476 AGTGCTCG GGCTAGCTACAACGA TCTTTGTT 3178

6738 AAGAACGA G CACUUCCU 1477 AGGAAGTG GGCTAGCTACAACGA TCGTTCTT 3179

6740 GAACGAGC A CUUCCUUU 1478 AAAGGAAG GGCTAGCTACAACGA GCTCGTTC 3180

6753 CUUUCAGA G UUUCUGAG 1479 CTCAGAAA GGCTAGCTACAACGA TCTGAAAG 3181

6762 UUUCUGAG A UAAUGUAC 1480 GTACATTA GGCTAGCTACAACGA CTCAGAAA 3182

6765 CUGAGAUA A UGUACGUG 1481 CACGTACA GGCTAGCTACAACGA TATCTCAG 3183

6767 GAGAUAAU G UACGUGGA 1482 TCCACGTA GGCTAGCTACAACGA ATTATCTC 3184

6769 GAUAAUGU A CGUGGAAC 1483 GTTCCACG GGCTAGCTACAACGA ACATTATC 3185

6771 UAAUGUAC G UGGAACAG 1484 CTGTTCCA GGCTAGCTACAACGA GTACATTA 3186

6776 UACGUGGA A CAGUCUGG 1485 CCAGACTG GGCTAGCTACAACGA TCCACGTA 3187

6779 GUGGAACA G UCUGGGUG 1486 CACCCAGA GGCTAGCTACAACGA TGTTCCAC 3188

6785 CAGUCUGG G UGGAAUGG 1487 CCATTCCA GGCTAGCTACAACGA CCAGACTG 3189

6790 UGGGUGGA A UGGGGCUG 1488 CAGCCCCA GGCTAGCTACAACGA TCCACCCA 3190

6795 GGAAUGGG G CUGAAACC 1489 GGTTTCAG GGCTAGCTACAACGA CCCATTCC 3191

6801 GGGCUGAA A CCAUGUGC 1490 GCACATGG GGCTAGCTACAACGA TTCAGCCC 3192

6804 CUGAAACC A UGUGCAAG 1491 CTTGCACA GGCTAGCTACAACGA GGTTTCAG 3193

6806 GAAACCAU G UGCAAGUC 1492 GACTTGCA GGCTAGCTACAACGA ATGGTTTC 3194

6808 AACCAUGU G CAAGUCUG 1493 CAGACTTG GGCTAGCTACAACGA ACATGGTT 3195

6812 AUGUGCAA G UCUGUGUC 1494 GACACAGA GGCTAGCTACAACGA TTGCACAT 3196

6816 GCAAGUCU G UGUCUUGU 1495 ACAAGACA GGCTAGCTACAACGA AGACTTGC 3197

6818 AAGUCUGU G UCUUGUCA 1496 TGACAAGA GGCTAGCTACAACGA ACAGACTT 3198

6823 UGUGUCUU G UCAGUCCA 1497 TGGACTGA GGCTAGCTACAACGA AAGACACA 3199

6827 UCUUGUCA G UCCAAGAA 1498 TTCTTGGA GGCTAGCTACAACGA TGACAAGA 3200

6836 UCCAAGAA G UGACACCG 1499 CGGTGTCA GGCTAGCTACAACGA TTCTTGGA 3201

6839 AAGAAGUG A CACCGAGA 1500 TCTCGGTG GGCTAGCTACAACGA CACTTCTT 3202

6841 GAAGUGAC A CCGAGAUG 1501 CATCTCGG GGCTAGCTACAACGA GTCACTTC 3203

6847 ACACCGAG A UGUUAAUU 1502 AATTAACA GGCTAGCTACAACGA CTCGGTGT 3204

6849 ACCGAGAU G UUAAUUUU 1503 AAAATTAA GGCTAGCTACAACGA ATCTCGGT 3205

6853 AGAUGUUA A UUUUAGGG 1504 CCCTAAAA GGCTAGCTACAACGA TAACATCT 3206 6862 UUUUAGGG A CCCGUGCC 1505 GGCACGGG GGCTAGCTACAACGA CCCTAAAA 3207

6866 AGGGACCC G UGCCUUGU 1506 ACAAGGCA GGCTAGCTACAACGA GGGTCCCT 3208

6868 GGACCCGU G CCUUGUUU 1507 AAACAAGG GGCTAGCTACAACGA ACGGGTCC 3209

6873 CGUGCCUU G UUUCCUAG 1508 CTAGGAAA GGCTAGCTACAACGA AAGGCACG 3210

6881 GUUUCCUA G CCCACAAG 1509 CTTGTGGG GGCTAGCTACAACGA TAGGAAAC 3211

6885 CCUAGCCC A CAAGAAUG 1510 CATTCTTG GGCTAGCTACAACGA GGGCTAGG 3212

6891 CCACAAGA A UGCAAACA 1511 TGTTTGCA GGCTAGCTACAACGA TCTTGTGG 3213

6893 ACAAGAAU G CAAACAUC 1512 GATGTTTG GGCTAGCTACAACGA ATTCTTGT 3214

6897 GAAUGCAA A CAUCAAAC 1513 GTTTGATG GGCTAGCTACAACGA TTGCATTC 3215

6899 AUGCAAAC A UCAAACAG 1514 CTGTTTGA GGCTAGCTACAACGA GTTTGCAT 3216

6904 AACAUCAA A CAGAUACU 1515 AGTATCTG GGCTAGCTACAACGA TTGATGTT 3217

6908 UCAAACAG A UACUCGCU 1516 AGCGAGTA GGCTAGCTACAACGA CTGTTTGA 3218

6910 AAACAGAU A CUCGCUAG 1517 CTAGCGAG GGCTAGCTACAACGA ATCTGTTT 3219

6914 AGAUACUC G CUAGCCUC 1518 GAGGCTAG GGCTAGCTACAACGA GAGTATCT 3220

6918 ACUCGCUA G CCUCAUUU 1519 AAATGAGG GGCTAGCTACAACGA TAGCGAGT 3221

6923 CUAGCCUC A UUUAAAUU 1520 AATTTAAA GGCTAGCTACAACGA GAGGCTAG 3222

6929 UCAUUUAA A UUGAUUAA 1521 TTAATCAA GGCTAGCTACAACGA TTAAATGA 3223

6933 UUAAAUUG A UUAAAGGA 1522 TCCTTTAA GGCTAGCTACAACGA CAATTTAA 3224

6945 AAGGAGGA G UGCAUCUU 1523 AAGATGCA GGCTAGCTACAACGA TCCTCCTT 3225

6947 GGAGGAGU G CAUCUUUG 1524 CAAAGATG GGCTAGCTACAACGA ACTCCTCC 3226

6949 AGGAGUGC A UCUUUGGC 1525 GCCAAAGA GGCTAGCTACAACGA GCACTCCT 3227

6956 CAUCUUUG G CCGACAGU 1526 ACTGTCGG GGCTAGCTACAACGA CAAAGATG 3228

6960 UUUGGCCG A CAGUGGUG 1527 CACCACTG GGCTAGCTACAACGA CGGCCAAA 3229

6963 GGCCGACA G UGGUGUAA 1528 TTACACCA GGCTAGCTACAACGA TGTCGGCC 3230

6966 CGACAGUG G UGUAACUG 1529 CAGTTACA GGCTAGCTACAACGA CACTGTCG 3231

6968 ACAGUGGU G UAACUGUG 1530 CACAGTTA GGCTAGCTACAACGA ACCACTGT 3232

6971 GUGGUGUA A CUGUGUGU 1531 ACACACAG GGCTAGCTACAACGA TACACCAC 3233

6974 GUGUAACU G UGUGUGUG 1532 CACACACA GGCTAGCTACAACGA AGTTACAC 3234

6976 GUAACUGU G UGUGUGUG 1533 CACACACA GGCTAGCTACAACGA ACAGTTAC 3235

6978 AACUGUGU G UGUGUGUG 1534 CACACACA GGCTAGCTACAACGA ACACAGTT 3236

6980 CUGUGUGU G UGUGUGUG 1535 CACACACA GGCTAGCTACAACGA ACACACAG 3237

6982 GUGUGUGU G UGUGUGUG 1536 CACACACA GGCTAGCTACAACGA ACACACAC 3238

6984 GUGUGUGU G UGUGUGUG 1537 CACACACA GGCTAGCTACAACGA ACACACAG 3239

6986 GUGUGUGU G UGUGUGUG 1538 CACACACA GGCTAGCTACAACGA ACACACAC 3240

6988 GUGUGUGU G UGUGUGUG 1539 CACACACA GGCTAGCTACAACGA ACACACAC 3241

6990 GUGUGUGU G UGUGUGUG 1540 CACACACA GGCTAGCTACAACGA ACACACAC 3242

6992 GUGUGUGU G UGUGUGUG 1541 CACACACA GGCTAGCTACAACGA ACACACAC 3243

6994 GUGUGUGU G UGUGUGUG 1542 CACACACA GGCTAGCTACAACGA ACACACAC 3244

6996 GUGUGUGU G UGUGUGUG 1543 CACACACA GGCTAGCTACAACGA ACACACAC 3245

6998 GUGUGUGU G UGUGUGUG 1544 CACACACA GGCTAGCTACAACGA ACACACAC 3246

7000 GUGUGUGU G UGUGUGUG 1545 CACACACA GGCTAGCTACAACGA ACACACAC 3247

7002 GUGUGUGU G UGUGUGUG 1546 CACACACA GGCTAGCTACAACGA ACACACAC 3248

7004 GUGUGUGU G UGUGUGUG 1547 CACACACA GGCTAGCTACAACGA ACACACAC 3249

7006 GUGUGUGU G UGUGUGUG 1548 CACACACA GGCTAGCTACAACGA ACACACAC 3250

7008 GUGUGUGU G UGUGUGGG 1549 CCCACACA GGCTAGCTACAACGA ACACACAC 3251

7010 GUGUGUGU G UGUGGGUG 1550 CACCCACA GGCTAGCTACAACGA ACACACAC 3252

7012 GUGUGUGU G UGGGUGUG 1551 CACACCCA GGCTAGCTACAACGA ACACACAC 3253

7016 GUGUGUGG G UGUGGGUG 1552 CACCCACA GGCTAGCTACAACGA CCACACAC 3254

7018 GUGUGGGU G UGGGUGUA 1553 TACACCCA GGCTAGCTACAACGA ACCCACAC 3255

7022 GGGUGUGG G UGUAUGUG 1554 CACATACA GGCTAGCTACAACGA CCACACCC 3256

7024 GUGUGGGU G UAUGUGUG 1555 CACACATA GGCTAGCTACAACGA ACCCACAC 3257

7026 GUGGGUGU A UGUGUGUU 1556 AACACACA GGCTAGCTACAACGA ACACCCAC 3258 7028 GGGUGUAU G UGUGUUUU 1557 AAAACACA GGCTAGCTACAACGA ATACACCC 3259

7030 GUGUAUGU G UGUUUUGU 1558 ACAAAACA GGCTAGCTACAACGA ACATACAC 3260

7032 GUAUGUGU G UUUUGUGC 1559 GCACAAAA GGCTAGCTACAACGA ACACATAC 3261

7037 UGUGUUUU G UGCAUAAC 1560 GTTATGCA GGCTAGCTACAACGA AAAACACA 3262

7039 UGUUUUGU G CAUAACUA 1561 TAGTTATG GGCTAGCTACAACGA ACAAAACA 3263

7041 UUUUGUGC A UAACUAUU 1562 AATAGTTA GGCTAGCTACAACGA GCACAAAA 3264

7044 UGUGCAUA A CUAUUUAA 1563 TTAAATAG GGCTAGCTACAACGA TATGCACA 3265

7047 GCAUAACU A UUUAAGGA 1564 TCCTTAAA GGCTAGCTACAACGA AGTTATGC 3266

7057 UUAAGGAA A CUGGAAUU 1565 AATTCCAG GGCTAGCTACAACGA TTCCTTAA 3267

7063 AAACUGGA A UUUUAAAG 1566 CTTTAAAA GGCTAGCTACAACGA TCCAGTTT 3268

7071 AUUUUAAA G UUACUUUU 1567 AAAAGTAA GGCTAGCTACAACGA TTTAAAAT 3269

7074 UUAAAGUU A CUUUUAUA 1568 TATAAAAG GGCTAGCTACAACGA AACTTTAA 3270

7080 UUACUUUU A UACAAACC 1569 GGTTTGTA GGCTAGCTACAACGA AAAAGTAA 3271

7082 ACUUUUAU A CAAACCAA 1570 TTGGTTTG GGCTAGCTACAACGA ATAAAAGT 3272

7086 UUAUACAA A CCAAGAAU 1571 ATTCTTGG GGCTAGCTACAACGA TTGTATAA 3273

7093 AACCAAGA A UAUAUGCU 1572 AGCATATA GGCTAGCTACAACGA TCTTGGTT 3274

7095 CCAAGAAU A UAUGCUAC 1573 GTAGCATA GGCTAGCTACAACGA ATTCTTGG 3275

7097 AAGAAUAU A UGCUACAG 1574 CTGTAGCA GGCTAGCTACAACGA ATATTCTT 3276

7099 GAAUAUAU G CUACAGAU 1575 ATCTGTAG GGCTAGCTACAACGA ATATATTC 3277

7102 UAUAUGCU A CAGAUAUA 1576 TATATCTG GGCTAGCTACAACGA AGCATATA 3278

7106 UGCUACAG A UAUAAGAC 1577 GTCTTATA GGCTAGCTACAACGA CTGTAGCA 3279

7108 CUACAGAU A UAAGACAG 1578 CTGTCTTA GGCTAGCTACAACGA ATCTGTAG 3280

7113 GAUAUAAG A CAGACAUG 1579 CATGTCTG GGCTAGCTACAACGA CTTATATC 3281

7117 UAAGACAG A CAUGGUUU 1580 AAACCATG GGCTAGCTACAACGA CTGTCTTA 3282

7119 AGACAGAC A UGGUUUGG 1581 CCAAACCA GGCTAGCTACAACGA GTCTGTCT 3283

7122 CAGACAUG G UUUGGUCC 1582 GGACCAAA GGCTAGCTACAACGA CATGTCTG 3284

7127 AUGGUUUG G UCCUAUAU 1583 ATATAGGA GGCTAGCTACAACGA CAAACCAT 3285

7132 UUGGUCCU A UAUUUCUA 1584 TAGAAATA GGCTAGCTACAACGA AGGACCAA 3286

7134 GGUCCUAU A UUUCUAGU 1585 ACTAGAAA GGCTAGCTACAACGA ATAGGACC 3287

7141 UAUUUCUA G UCAUGAUG 1586 CATCATGA GGCTAGCTACAACGA TAGAAATA 3288

7144 UUCUAGUC A UGAUGAAU 1587 ATTCATGA GGCTAGCTACAACGA GACTAGAA 3289

7147 UAGUCAUG A UGAAUGUA 1588 TACATTCA GGCTAGCTACAACGA CATGACTA 3290

7151 CAUGAUGA A UGUAUUUU 1589 AAAATACA GGCTAGCTACAACGA TCATCATG 3291

7153 UGAUGAAU G UAUUUUGU 1590 ACAAAATA GGCTAGCTACAACGA ATTCATCA 3292

7155 AUGAAUGU A UUUUGUAU 1591 ATACAAAA GGCTAGCTACAACGA ACATTCAT 3293

7160 UGUAUUUU G UAUACCAU 1592 ATGGTATA GGCTAGCTACAACGA AAAATACA 3294

7162 UAUUUUGU A UACCAUCU 1593 AGATGGTA GGCTAGCTACAACGA ACAAAATA 3295

7164 UUUUGUAU A CCAUCUUC 1594 GAAGATGG GGCTAGCTACAACGA ATACAAAA 3296

7167 UGUAUACC A UCUUCAUA 1595 TATGAAGA GGCTAGCTACAACGA GGTATACA 3297

7173 CCAUCUUC A UAUAAUAU 1596 ATATTATA GGCTAGCTACAACGA GAAGATGG 3298

7175 AUCUUCAU A UAAUAUAC 1597 GTATATTA GGCTAGCTACAACGA ATGAAGAT 3299

7178 UUCAUAUA A UAUACUUA 1598 TAAGTATA GGCTAGCTACAACGA TATATGAA 3300

7180 CAUAUAAU A UACUUAAA 1599 TTTAAGTA GGCTAGCTACAACGA ATTATATG 3301

7182 UAUAAUAU A CUUAAAAA 1600 TTTTTAAG GGCTAGCTACAACGA ATATTATA 3302

7190 ACUUAAAA A UAUUUCUU 1601 AAGAAATA GGCTAGCTACAACGA TTTTAAGT 3303

7192 UUAAAAAU A UUUCUUAA 1602 TTAAGAAA GGCTAGCTACAACGA ATTTTTAA 3304

7200 AUUUCUUA A UUGGGAUU 1603 AATCCCAA GGCTAGCTACAACGA TAAGAAAT 3305

7206 UAAUUGGG A UUUGUAAU 1604 ATTACAAA GGCTAGCTACAACGA CCCAATTA 3306

7210 UGGGAUUU G UAAUCGUA 1605 TACGATTA GGCTAGCTACAACGA AAATCCCA 3307

7213 GAUUUGUA A UCGUACCA 1606 TGGTACGA GGCTAGCTACAACGA TACAAATC 3308

7216 UUGUAAUC G UACCAACU 1607 AGTTGGTA GGCTAGCTACAACGA GATTACAA 3309

7218 GUAAUCGU A CCAACUUA 1608 TAAGTTGG GGCTAGCTACAACGA ACGATTAC 3310 7222 UCGUACCA A CUUAAUUG 1609 CAATTAAG GGCTAGCTACAACGA TGGTACGA 3311

7227 CCAACUUA A UUGAUAAA 1610 TTTATCAA GGCTAGCTACAACGA TAAGTTGG 3312

7231 CUUAAUUG A UAAACUUG 1611 CAAGTTTA GGCTAGCTACAACGA CAATTAAG 3313

7235 AUUGAUAA A CUUGGCAA 1612 TTGCCAAG GGCTAGCTACAACGA TTATCAAT 3314

7240 UAAACUUG G CAACUGCU 1613 AGCAGTTG GGCTAGCTACAACGA CAAGTTTA 3315

7243 ACUUGGCA A CUGCUUUU 1614 AAAAGCAG GGCTAGCTACAACGA TGCCAAGT 3316

7246 UGGCAACU G CUUUUAUG 1615 CATAAAAG GGCTAGCTACAACGA AGTTGCCA 3317

7252 CUGCUUUU A UGUUCUGU 1616 ACAGAACA GGCTAGCTACAACGA AAAAGCAG 3318

7254 GCUUUUAU G UUCUGUCU 1617 AGACAGAA GGCTAGCTACAACGA ATAAAAGC 3319

7259 UAUGUUCU G UCUCCUUC 1618 GAAGGAGA GGCTAGCTACAACGA AGAACATA 3320

7269 CUCCUUCC A UAAAUUUU 1619 AAAATTTA GGCTAGCTACAACGA GGAAGGAG 3321

7273 UUCCAUAA A UUUUUCAA 1620 TTGAAAAA GGCTAGCTACAACGA TTATGGAA 3322

7283 UUUUCAAA A UACUAAUU 1621 AATTAGTA GGCTAGCTACAACGA TTTGAAAA 3323

7285 UUCAAAAU A CUAAUUCA 1622 TGAATTAG GGCTAGCTACAACGA ATTTTGAA 3324

7289 AAAUACUA A UUCAACAA 1623 TTGTTGAA GGCTAGCTACAACGA TAGTATTT 3325

7294 CUAAUUCA A CAAAGAAA 1624 TTTCTTTG GGCTAGCTACAACGA TGAATTAG 3326

7305 AAGAAAAA G CUCUUUUU 1625 AAAAAGAG GGCTAGCTACAACGA TTTTTCTT 3327

7323 UUCCUAAA A UAAACUCA 1626 TGAGTTTA GGCTAGCTACAACGA TTTAGGAA 3328

7327 UAAAAUAA A CUCAAAUU 1627 AATTTGAG GGCTAGCTACAACGA TTATTTTA 3329

7333 AAACUCAA A UUUAUCCU 1628 AGGATAAA GGCTAGCTACAACGA TTGAGTTT 3330

7337 UCAAAUUU A UCCUUGUU 1629 AACAAGGA GGCTAGCTACAACGA AAATTTGA 3331

7343 UUAUCCUU G UUUAGAGC 1630 GCTCTAAA GGCTAGCTACAACGA AAGGATAA 3332

7350 UGUUUAGA G CAGAGAAA 1631 TTTCTCTG GGCTAGCTACAACGA TCTAAACA 3333

7360 AGAGAAAA A UUAAGAAA 1632 TTTCTTAA GGCTAGCTACAACGA TTTTCTCT 3334

7370 UAAGAAAA A CUUUGAAA 1633 TTTCAAAG GGCTAGCTACAACGA TTTTCTTA 3335

7378 ACUUUGAA A UGGUCUCA 1634 TGAGACCA GGCTAGCTACAACGA TTCAAAGT 3336

7381 UUGAAAUG G UCUCAAAA 1635 TTTTGAGA GGCTAGCTACAACGA CATTTCAA 3337

7391 CUCAAAAA A UUGCUAAA 1636 TTTAGCAA GGCTAGCTACAACGA TTTTTGAG 3338

7394 AAAAAAUU G CUAAAUAU 1637 ATATTTAG GGCTAGCTACAACGA AATTTTTT 3339

7399 AUUGCUAA A UAUUUUCA 1638 TGAAAATA GGCTAGCTACAACGA TTAGCAAT 3340

7401 UGCUAAAU A UUUUCAAU 1639 ATTGAAAA GGCTAGCTACAACGA ATTTAGCA 3341

7408 UAUUUUCA A UGGAAAAC 1640 GTTTTCCA GGCTAGCTACAACGA TGAAAATA 3342

7415 AAUGGAAA A CUAAAUGU 1641 AGATTTAG GGCTAGCTACAACGA TTTCCATT 3343

7420 AAAACUAA A UGUUAGUU 1642 AACTAACA GGCTAGCTACAACGA TTAGTTTT 3344

7422 AACUAAAU G UUAGUUUA 1643 TAAACTAA GGCTAGCTACAACGA ATTTAGTT 3345

7426 AAAUGUUA G UUUAGCUG 1644 CAGCTAAA GGCTAGCTACAACGA TAACATTT 3346

7431 UUAGUUUA G CUGAUUGU 1645 ACAATCAG GGCTAGCTACAACGA TAAACTAA 3347

7435 UUUAGCUG A UUGUAUGG 1646 CCATACAA GGCTAGCTACAACGA CAGCTAAA 3348

7438 AGCUGAUU G UAUGGGGU 1647 ACCCCATA GGCTAGCTACAACGA AATCAGCT 3349

7440 CUGAUUGU A UGGGGUUU 1648 AAACCCCA GGCTAGCTACAACGA ACAATCAG 3350

7445 UGUAUGGG G UUUUCGAA 1649 TTCGAAAA GGCTAGCTACAACGA CCCATACA 3351

7453 GUUUUCGA A CCUUUCAC 1650 GTGAAAGG GGCTAGCTACAACGA TCGAAAAC 3352

7460 AACCUUUC A CUUUUUGU 1651 ACAAAAAG GGCTAGCTACAACGA GAAAGGTT 3353

7467 CACUUUUU G UUUGUUUU 1652 AAAACAAA GGCTAGCTACAACGA AAAAAGTG 3354

7471 UUUUGUUU G UUUUACCU 1653 AGGTAAAA GGCTAGCTACAACGA AAACAAAA 3355

7476 UUUGUUUU A CCUAUUUC 1654 GAAATAGG GGCTAGCTACAACGA AAAACAAA 3356

7480 UUUUACCU A UUUCACAA 1655 TTGTGAAA GGCTAGCTACAACGA AGGTAAAA 3357

7485 CCUAUUUC A CAACUGUG 1656 CACAGTTG GGCTAGCTACAACGA GAAATAGG 3358

7488 AUUUCACA A CUGUGUAA 1657 TTACACAG GGCTAGCTACAACGA TGTGAAAT 3359

7491 UCACAACU G UGUAAAUU 1658 AATTTACA GGCTAGCTACAACGA AGTTGTGA 3360

7493 ACAACUGU G UAAAUUGC 1659 GCAATTTA GGCTAGCTACAACGA ACAGTTGT 3361

7497 CUGUGUAA A UUGCCAAU 1660 ATTGGCAA GGCTAGCTACAACGA TTACACAG 3362 7500 UGUAAAUU G CCAAUAAU 1661 ATTATTGG GGCTAGCTACAACGA AATTTACA 3363

7504 AAUUGCCA A UAAUUCCU 1662 AGGAATTA GGCTAGCTACAACGA TGGCAATT 3364

7507 UGCCAAUA A UUCCUGUC 1663 GACAGGAA GGCTAGCTACAACGA TATTGGCA 3365

7513 UAAUUCCU G UCCAUGAA 1664 TTCATGGA GGCTAGCTACAACGA AGGAATTA 3366

7517 UCCUGUCC A UGAAAAUG 1665 CATTTTCA GGCTAGCTACAACGA GGACAGGA 3367

7523 CCAUGAAA A UGCAAAUU 1666 AATTTGCA GGCTAGCTACAACGA TTTCATGG 3368

7525 AUGAAAAU G CAAAUUAU 1667 ATAATTTG GGCTAGCTACAACGA ATTTTCAT 3369

7529 AAAUGCAA A UUAUCCAG 1668 CTGGATAA GGCTAGCTACAACGA TTGCATTT 3370

7532 UGCAAAUU A UCCAGUGU 1669 ACACTGGA GGCTAGCTACAACGA AATTTGCA 3371

7537 AUUAUCCA G UGUAGAUA 1670 TATCTACA GGCTAGCTACAACGA TGGATAAT 3372

7539 UAUCCAGU G UAGAUAUA 1671 TATATCTA GGCTAGCTACAACGA ACTGGATA 3373

7543 CAGUGUAG A UAUAUUUG 1672 CAAATATA GGCTAGCTACAACGA CTACACTG 3374

7545 GUGUAGAU A UAUUUGAC 1673 GTCAAATA GGCTAGCTACAACGA ATCTACAC 3375

7547 GUAGAUAU A UUUGACCA 1674 TGGTCAAA GGCTAGCTACAACGA ATATCTAC 3376

7552 UAUAUUUG A CCAUCACC 1675 GGTGATGG GGCTAGCTACAACGA CAAATATA 3377

7555 AUUUGACC A UCACCCUA 1676 TAGGGTGA GGCTAGCTACAACGA GGTCAAAT 3378

7558 UGACCAUC A CCCUAUGG 1677 CCATAGGG GGCTAGCTACAACGA GATGGTCA 3379

7563 AUCACCCU A UGGAUAUU 1678 AATATCCA GGCTAGCTACAACGA AGGGTGAT 3380

7567 CCCUAUGG A UAUUGGCU 1679 AGCCAATA GGCTAGCTACAACGA CCATAGGG 3381

7569 CUAUGGAU A UUGGCUAG 1680 CTAGCCAA GGCTAGCTACAACGA ATCCATAG 3382

7573 GGAUAUUG G CUAGUUUU 1681 AAAACTAG GGCTAGCTACAACGA CAATATCC 3383

7577 AUUGGCUA G UUUUGCCU 1682 AGGCAAAA GGCTAGCTACAACGA TAGCCAAT 3384

7582 CUAGUUUU G CCUUUAUU 1683 AATAAAGG GGCTAGCTACAACGA AAAACTAG 3385

7588 UUGCCUUU A UUAAGCAA 1684 TTGCTTAA GGCTAGCTACAACGA AAAGGCAA 3386

7593 UUUAUUAA G CAAAUUCA 1685 TGAATTTG GGCTAGCTACAACGA TTAATAAA 3387

7597 UUAAGCAA A UUCAUUUC 1686 GAAATGAA GGCTAGCTACAACGA TTGCTTAA 3388

7601 GCAAAUUC A UUUCAGCC 1687 GGCTGAAA GGCTAGCTACAACGA GAATTTGC 3389

7607 UCAUUUCA G CCUGAAUG 1688 CATTCAGG GGCTAGCTACAACGA TGAAATGA 3390

7613 CAGCCUGA A UGUCUGCC 1689 GGCAGACA GGCTAGCTACAACGA TCAGGCTG 3391

7615 GCCUGAAU G UCUGCCUA 1690 TAGGCAGA GGCTAGCTACAACGA ATTCAGGC 3392

7619 GAAUGUCU G CCUAUAUA 1691 TATATAGG GGCTAGCTACAACGA AGACATTC 3393

7623 GUCUGCCU A UAUAUUCU 1692 AGAATATA GGCTAGCTACAACGA AGGCAGAC 3394

7625 CUGCCUAU A UAUUCUCU 1693 AGAGAATA GGCTAGCTACAACGA ATAGGCAG 3395

7627 GCCUAUAU A UUCUCUGC 1694 GCAGAGAA GGCTAGCTACAACGA ATATAGGC 3396

7634 UAUUCUCU G CUCUUUGU 1695 ACAAAGAG GGCTAGCTACAACGA AGAGAATA 3397

7641 UGCUCUUU G UAUUCUCC 1696 GGAGAATA GGCTAGCTACAACGA AAAGAGCA 3398

7643 CUCUUUGU A UUCUCCUU 1697 AAGGAGAA GGCTAGCTACAACGA ACAAAGAG 3399

7655 UCCUUUGA A CCCGUUAA 1698 TTAACGGG GGCTAGCTACAACGA TCAAAGGA 3400

7659 UUGAACCC G UUAAAACA 1699 TGTTTTAA GGCTAGCTACAACGA GGGTTCAA 3401

7665 CCGUUAAA A CAUCCUGU 1700 ACAGGATG GGCTAGCTACAACGA TTTAACGG 3402

7667 GUUAAAAC A UCCUGUGG 1701 CCACAGGA GGCTAGCTACAACGA GTTTTAAC 3403

7672 AACAUCCU G UGGCACUC 1702 GAGTGCCA GGCTAGCTACAACGA AGGATGTT 3404

Input Sequence = HSFLT. Cut Site = R/Y

Arm Length = 8. Core Sequence = GGCTAGCTACAACGA

HSFLT (Human fit mRNA for receptor-related tyrosine kinase.; Acc# X51602; 7680 bp) Table VI: Human KDR DNAzyme and Substrate sequence

Pos Substrate SeqlD DNAzyme SeqlD

No No

14 GUCCCGGG A CCCCGGGA 3405 TCCCGGGG GGCTAGCTACAACGA CCCGGGAC 4691

25 CCGGGAGA G CGGUCAGU 3406 ACTGACCG GGCTAGCTACAACGA TCTCCCGG 4692

28 GGAGAGCG G UCAGUGUG 3407 CACACTGA GGCTAGCTACAACGA CGCTCTCC 4693

32 AGCGGUCA G UGUGUGGU 3408 ACCACACA GGCTAGCTACAACGA TGACCGCT 4694

34 CGGUCAGU G UGUGGUCG 3409 CGACCACA GGCTAGCTACAACGA ACTGACCG 4695

36 GUCAGUGU G UGGUCGCU 3410 AGCGACCA GGCTAGCTACAACGA ACACTGAC 4696

39 AGUGUGUG G UCGCUGCG 3411 CGCAGCGA GGCTAGCTACAACGA CACACACT 4697

42 GUGUGGUC G CUGCGUUU 3412 AAACGCAG GGCTAGCTACAACGA GACCACAC 4698

45 UGGUCGCU G CGUUUCCU 3413 AGGAAACG GGCTAGCTACAACGA AGCGACCA 4699

47 GUCGCUGC G UUUCCUCU 3414 AGAGGAAA GGCTAGCTACAACGA GCAGCGAC 4700

56 UUUCCUCU G CCUGCGCC 3415 GGCGCAGG GGCTAGCTACAACGA AGAGGAAA 4701

60 CUCUGCCU G CGCCGGGC 3416 GCCCGGCG GGCTAGCTACAACGA AGGCAGAG 4702

62 CUGCCUGC G CCGGGCAU 3417 ATGCCCGG GGCTAGCTACAACGA GCAGGCAG 4703

67 UGCGCCGG G CAUCACUU 3418 AAGTGATG GGCTAGCTACAACGA CCGGCGCA 4704

69 CGCCGGGC A UCACUUGC 3419 GCAAGTGA GGCTAGCTACAACGA GCCCGGCG 4705

72 CGGGCAUC A CUUGCGCG 3420 CGCGCAAG GGCTAGCTACAACGA GATGCCCG 4706

!(.^' jAUCACUU G CGCGCCGC 3421 GCGGCGCG GGCTAGCTACAACGA AAGTGATG 4707

78 ^~ UCACUUGC G CGCCGCAG 3422 CTGCGGCG GGCTAGCTACAACGA GCAAGTGA 4708

80 ACUUGCGC G CCGCAGAA 3423 TTCTGCGG GGCTAGCTACAACGA GCGCAAGT 4709

83 UGCGCGCC G CAGAAAGU 3424 ACTTTCTG GGCTAGCTACAACGA GGCGCGCA 4710

90 GGCAGAAA G UCCGUCUG 3425 CAGACGGA GGCTAGCTACAACGA TTTCTGCG 4711

94 GAAAGUCC G UCUGGCAG 3426 CTGCCAGA GGCTAGCTACAACGA GGACTTTC 4712

99 UCCGUCUG G CAGCCUGG 3427 CCAGGCTG GGCTAGCTACAACGA CAGACGGA 4713

102 GUCUGGCA G CCUGGAUA 3428 TATCCAGG GGCTAGCTACAACGA TGCCAGAC 4714

108 CAGCCUGG A UAUCCUCU 3429 AGAGGATA GGCTAGCTACAACGA CCAGGCTG 4715

110 GCCUGGAU A UCCUCUCC 3430 GGAGAGGA GGCTAGCTACAACGA ATCCAGGC 4716

120 CCUCUCCU A CCGGCACC 3431 GGTGCCGG GGCTAGCTACAACGA AGGAGAGG 4717

124 UCCUACCG G CACCCGCA 3432 TGCGGGTG GGCTAGCTACAACGA CGGTAGGA 4718

126 CUACCGGC A CCCGCAGA 3433 TCTGCGGG GGCTAGCTACAACGA GCCGGTAG 4719

130 CGGCACCC G CAGACGCC 3434 GGCGTCTG GGCTAGCTACAACGA GGGTGCCG 4720

134 ACCCGCAG A CGCCCCUG 3435 CAGGGGCG GGCTAGCTACAACGA CTGCGGGT 4721

136 CCGCAGAC G CCCCUGCA 3436 TGCAGGGG GGCTAGCTACAACGA GTCTGCGG 4722

142 ACGCCCCU G CAGCCGCC 3437 GGCGGCTG GGCTAGCTACAACGA AGGGGCGT 4723

145 CCCCUGCA G CCGCCGGU 3438 ACCGGCGG GGCTAGCTACAACGA TGCAGGGG 4724

148 CUGCAGCC G CCGGUCGG 3439 CCGACCGG GGCTAGCTACAACGA GGCTGCAG 4725

152 AGCCGCCG G UCGGCGCC 3440 GGCGCCGA GGCTAGCTACAACGA CGGCGGCT 4726

156 GCCGGUCG G CGCCCGGG 3441 CCCGGGCG GGCTAGCTACAACGA CGACCGGC 4727

158 CGGUCGGC G CCCGGGCU 3442 AGCCCGGG GGCTAGCTACAACGA GCCGACCG 4728

164 GCGCCCGG G CUCCCUAG 3443 CTAGGGAG GGCTAGCTACAACGA CCGGGCGC 4729

172 GCUCCCUA G CCCUGUGC 3444 GCACAGGG GGCTAGCTACAACGA TAGGGAGC 4730

177 CUAGCCCU G UGCGCUCA 3445 TGAGCGCA GGCTAGCTACAACGA AGGGCTAG 4731

179 AGCCCUGU G CGCUCAAC 3446 GTTGAGCG GGCTAGCTACAACGA ACAGGGCT 4732

181 CCCUGUGC G CUCAACUG 3447 CAGTTGAG GGCTAGCTACAACGA GCACAGGG 4733

186 UGCGCUCA A CUGUCCUG 3448 CAGGACAG GGCTAGCTACAACGA TGAGCGCA 4734

189 GCUCAACU G UCCUGCGC 3449 GCGCAGGA GGCTAGCTACAACGA AGTTGAGC 4735

194 ACUGUCCU G CGCUGCGG 3450 CCGCAGCG GGCTAGCTACAACGA AGGACAGT 4736

196 UGUCCUGC G CUGCGGGG 3451 CCCCGCAG GGCTAGCTACAACGA GCAGGACA 4737

199 CCUGCGCU G CGGGGUGC 3452 GCACCCCG GGCTAGCTACAACGA AGCGCAGG 4738

204 GCUGCGGG G UGCCGCGA 3453 TCGCGGCA GGCTAGCTACAACGA CCCGCAGC 4739 206 UGCGGGGU G CCGCGAGU 3454 ACTCGCGG GGCTAGCTACAACGA ACCCCGCA 4740

209 GGGGUGCC G CGAGUUCC 3455 GGAACTCG GGCTAGCTACAACGA GGCACCCC 4741

213 UGCCGCGA G UUCCACCU 3456 AGGTGGAA GGCTAGCTACAACGA TCGCGGCA 4742

218 CGAGUUCC A CCUCCGCG 3457 CGCGGAGG GGCTAGCTACAACGA GGAACTCG 4743

224 CCACCUCC G CGCCUCCU 3458 AGGAGGCG GGCTAGCTACAACGA GGAGGTGG 4744

226 ACCUCCGC G CCUCCUUC 3459 GAAGGAGG GGCTAGCTACAACGA GCGGAGGT 4745

240 UUCUCUAG A CAGGCGCU 3460 AGCGCCTG GGCTAGCTACAACGA CTAGAGAA 4746

244 CUAGACAG G CGCUGGGA 3461 TCCCAGCG GGCTAGCTACAACGA CTGTCTAG 4747

246 AGACAGGC G CUGGGAGA 3462 TCTCCCAG GGCTAGCTACAACGA GCCTGTCT 4748

259 GAGAAAGA A CCGGCUCC 3463 GGAGCCGG GGCTAGCTACAACGA TCTTTCTC 4749

263 AAGAACCG G CUCCCGAG 3464 CTCGGGAG GGCTAGCTACAACGA CGGTTCTT 4750

271 GCUCCCGA G UUCUGGGC 3465 GCCCAGAA GGCTAGCTACAACGA TCGGGAGC 4751

278 AGUUCUGG G CAUUUGGC 3466 GCGAAATG GGCTAGCTACAACGA CCAGAACT 4752

280 UUCUGGGC A UUUCGCCC 3467 GGGCGAAA GGCTAGCTACAACGA GCCCAGAA 4753

285 GGCAUUUC G CCCGGCUC 3468 GAGCCGGG GGCTAGCTACAACGA GAAATGCC 4754

290 UUCGCCCG G CUCGAGGU 3469 ACCTCGAG GGCTAGCTACAACGA CGGGCGAA 4755

297 GGCUCGAG G UGCAGGAU 3470 ATCCTGCA GGCTAGCTACAACGA CTCGAGCC 4756

299 CUCGAGGU G CAGGAUGC 3471 GCATCCTG GGCTAGCTACAACGA ACCTCGAG 4757

304 GGUGCAGG A UGCAGAGC 3472 GCTCTGCA GGCTAGCTACAACGA CCTGCACC 4758

306 UGCAGGAU G CAGAGCAA 3473 TTGCTCTG GGCTAGCTACAACGA ATCCTGCA 4759

311 GAUGCAGA G CAAGGUGC 3474 GCACCTTG GGCTAGCTACAACGA TCTGCATC 4760

316 AGAGCAAG G UGCUGCUG 3475 CAGCAGCA GGCTAGCTACAACGA CTTGCTCT 4761

318 AGCAAGGU G CUGCUGGC 3476 GCCAGCAG GGCTAGCTACAACGA ACCTTGCT 4762

321 AAGGUGCU G CUGGCCGU 3477 ACGGCCAG GGCTAGCTACAACGA AGCACCTT 4763

325 UGCUGCUG G CCGUCGCC 3478 GGCGACGG GGCTAGCTACAACGA CAGCAGCA 4764

328 UGCUGGCC G UCGCCCUG 3479 CAGGGCGA GGCTAGCTACAACGA GGCCAGCA 4765

331 UGGCCGUC G CCCUGUGG 3480 CCACAGGG GGCTAGCTACAACGA GACGGCCA 4766

336 GUCGCCCU G UGGCUCUG 3481 CAGAGCCA GGCTAGCTACAACGA AGGGCGAC 4767

339 GCCCUGUG G CUCUGCGU 3482 ACGCAGAG GGCTAGCTACAACGA CACAGGGC 4768

344 GUGGCUCU G CGUGGAGA 3483 TCTCCACG GGCTAGCTACAACGA AGAGCCAG 4769

346 GGCUCUGC G UGGAGACC 3484 GGTCTCCA GGCTAGCTACAACGA GCAGAGCC 4770

352 GCGUGGAG A CCCGGGCC 3485 GGCCCGGG GGCTAGCTACAACGA CTCCACGC 4771

358 AGACCCGG G CCGCCUCU 3486 AGAGGCGG GGCTAGCTACAACGA CCGGGTCT 4772

361 CCCGGGCC G CCUCUGUG 3487 CACAGAGG GGCTAGCTACAACGA GGCCCGGG 4773

367 CCGCCUCU G UGGGUUUG 3488 CAAACCCA GGCTAGCTACAACGA AGAGGCGG 4774

371 CUCUGUGG G UUUGCCUA 3489 TAGGCAAA GGCTAGCTACAACGA CCACAGAG 4775

375 GUGGGUUU G CCUAGUGU 3490 ACACTAGG GGCTAGCTACAACGA AAACCCAC 4776

380 UUUGCCUA G UGUUUCUC 3491 GAGAAACA GGCTAGCTACAACGA TAGGCAAA 4777

382 UGCCUAGU G UUUCUCUU 3492 AAGAGAAA GGCTAGCTACAACGA ACTAGGCA 4778

392 UUCUCUUG A UCUGCCCA 3493 TGGGCAGA GGCTAGCTACAACGA CAAGAGAA 4779

396 CUUGAUCU G CCCAGGCU 3494 AGCCTGGG GGCTAGCTACAACGA AGATCAAG 4780

402 CUGCCCAG G CUCAGCAU 3495 ATGCTGAG GGCTAGCTACAACGA CTGGGCAG 4781

407 CAGGCUCA G CAUACAAA 3496 TTTGTATG GGCTAGCTACAACGA TGAGCCTG 4782

409 GGCUCAGC A UACAAAAA 3497 TTTTTGTA GGCTAGCTACAACGA GCTGAGCC 4783

411 CUCAGGAU A CAAAAAGA 3498 TCTTTTTG GGCTAGCTACAACGA ATGCTGAG 4784

419 ACAAAAAG A CAUACUUA 3499 TAAGTATG GGCTAGCTACAACGA CTTTTTGT 4785

421 AAAAAGAC A UACUUACA 3500 TGTAAGTA GGCTAGCTACAACGA GTCTTTTT 4786

423 AAAGACAU A CUUACAAU 3501 ATTGTAAG GGCTAGCTACAACGA ATGTCTTT 4787

427 ACAUACUU A CAAUUAAG 3502 CTTAATTG GGCTAGCTACAACGA AAGTATGT 4788

430 UACUUACA A UUAAGGCU 3503 AGCCTTAA GGCTAGCTACAACGA TGTAAGTA 4789

436 CAAUUAAG G CUAAUACA 3504 TGTATTAG GGCTAGCTACAACGA CTTAATTG 4790

440 UAAGGCUA A UACAACUC 3505 GAGTTGTA GGCTAGCTACAACGA TAGCCTTA 4791

442 AGGCUAAU A CAACUCUU 3506 AAGAGTTG GGCTAGCTACAACGA ATTAGCCT 4792 445 CUAAUACA A CUCUUCAA 3507 TTGAAGAG GGCTAGCTACAACGA TGTATTAG 4793

454 CUCUUCAA A UUACUUGC 3508 GCAAGTAA GGCTAGCTACAACGA TTGAAGAG 4794

457 UUCAAAUU A CUUGCAGG 3509 CCTGCAAG GGCTAGCTACAACGA AATTTGAA 4795

461 AAUUACUU G CAGGGGAC 3510 GTCCCCTG GGCTAGCTACAACGA AAGTAATT 4796

468 UGCAGGGG A CAGAGGGA 3511 TCCCTCTG GGCTAGCTACAACGA CCCCTGCA 4797

476 ACAGAGGG A CUUGGACU 3512 AGTCCAAG GGCTAGCTACAACGA CCCTCTGT 4798

482 GGACUUGG A CUGGCUUU 3513 AAAGCCAG GGCTAGCTACAACGA CCAAGTCC 4799

486 UUGGACUG G CUUUGGCC 3514 GGCCAAAG GGCTAGCTACAACGA CAGTCCAA 4800

492 UGGCUUUG G CCCAAUAA 3515 TTATTGGG GGCTAGCTACAACGA CAAAGCCA 4801

497 UUGGCCCA A UAAUCAGA 3516 TCTGATTA GGCTAGCTACAACGA TGGGCCAA 4802

500 GCCCAAUA A UCAGAGUG 3517 CACTCTGA GGCTAGCTACAACGA TATTGGGC 4803

506 UAAUCAGA G UGGCAGUG 3518 CACTGCCA GGCTAGCTACAACGA TCTGATTA 4804

509 UCAGAGUG G CAGUGAGC 3519 GCTCACTG GGCTAGCTACAACGA CACTCTGA 4805

512 GAGUGGCA G UGAGCAAA 3520 TTTGCTCA GGCTAGCTACAACGA TGCCACTC 4806

516 GGCAGUGA G CAAAGGGU 3521 ACCCTTTG GGCTAGCTACAACGA TCACTGCC 4807

523 AGCAAAGG G UGGAGGUG 3522 CACCTCCA GGCTAGCTACAACGA CCTTTGCT 4808

529 GGGUGGAG G UGACUGAG 3523 CTCAGTCA GGCTAGCTACAACGA CTCCACCC 4809

532 UGGAGGUG A CUGAGUGC 3524 GCACTCAG GGCTAGCTACAACGA CACCTCCA 4810

537 GUGACUGA G UGCAGCGA 3525 TCGCTGCA GGCTAGCTACAACGA TCAGTCAC 4811

539 GACUGAGU G CAGCGAUG 3526 CATCGCTG GGCTAGCTACAACGA ACTCAGTC 4812

542 UGAGUGCA G CGAUGGCC 3527 GGCCATCG GGCTAGCTACAACGA TGCACTCA 4813

545 GUGCAGCG A UGGCCUCU 3528 AGAGGCCA GGCTAGCTACAACGA CGCTGCAC 4814

548 CAGCGAUG G CCUCUUCU 3529 AGAAGAGG GGCTAGCTACAACGA CATCGCTG 4815

557 CCUCUUCU G UAAGACAC 3530 GTGTCTTA GGCTAGCTACAACGA AGAAGAGG 4816

562 UCUGUAAG A CACUCACA 3531 TGTGAGTG GGCTAGCTACAACGA CTTACAGA 4817

564 UGUAAGAC A CUCACAAU 3532 ATTGTGAG GGCTAGCTACAACGA GTCTTACA 4818

568 AGACACUC A CAAUUCCA 3533 TGGAATTG GGCTAGCTACAACGA GAGTGTCT 4819

571 CACUCACA A UUCCAAAA 3534 TTTTGGAA GGCTAGCTACAACGA TGTGAGTG 4820

580 UUCCAAAA G UGAUCGGA 3535 TCCGATCA GGCTAGCTACAACGA TTTTGGAA 4821

583 CAAAAGUG A UCGGAAAU 3536 ATTTCCGA GGCTAGCTACAACGA CACTTTTG 4822

590 GAUCGGAA A UGACACUG 3537 CAGTGTCA GGCTAGCTACAACGA TTCCGATC 4823

593 CGGAAAUG A CACUGGAG 3538 CTCCAGTG GGCTAGCTACAACGA CATTTCCG 4824

595 GAAAUGAC A CUGGAGCC 3539 GGCTCCAG GGCTAGCTACAACGA GTCATTTC 4825

601 ACACUGGA G CCUACAAG 3540 CTTGTAGG GGCTAGCTACAACGA TCCAGTGT 4826

605 UGGAGCCU A CAAGUGCU 3541 AGCACTTG GGCTAGCTACAACGA AGGCTCCA 4827

609 GCCUACAA G UGCUUCUA 3542 TAGAAGCA GGCTAGCTACAACGA TTGTAGGC 4828

611 CUACAAGU G CUUCUACC 3543 GGTAGAAG GGCTAGCTACAACGA ACTTGTAG 4829

617 GUGCUUCU A CCGGGAAA 3544 TTTCCCGG GGCTAGCTACAACGA AGAAGCAC 4830

625 ACCGGGAA A CUGACUUG 3545 CAAGTCAG GGCTAGCTACAACGA TTCCCGGT 4831

629 GGAAACUG A CUUGGCCU 3546 AGGCCAAG GGCTAGCTACAACGA CAGTTTCC 4832

634 CUGACUUG G CCUCGGUC 3547 GACCGAGG GGCTAGCTACAACGA CAAGTCAG 4833

640 UGGCCUCG G UCAUUUAU 3548 ATAAATGA GGCTAGCTACAACGA CGAGGCCA 4834

643 CCUCGGUC A UUUAUGUC 3549 GACATAAA GGCTAGCTACAACGA GACCGAGG 4835

647 GGUCAUUU A UGUCUAUG 3550 CATAGACA GGCTAGCTACAACGA AAATGACC 4836

649 UCAUUUAU G UCUAUGUU 3551 AAGATAGA GGCTAGCTACAACGA ATAAATGA 4837

653 UUAUGUCU A UGUUCAAG 3552 CTTGAACA GGCTAGCTACAACGA AGACATAA 4838

655 AUGUCUAU G UUCAAGAU 3553 ATCTTGAA GGCTAGCTACAACGA ATAGACAT 4839

662 UGUUCAAG A UUACAGAU 3554 ATCTGTAA GGCTAGCTACAACGA CTTGAACA 4840

665 UCAAGAUU A CAGAUCUC 3555 GAGATCTG GGCTAGCTACAACGA AATCTTGA 4841

669 GAUUACAG A UCUCCAUU 3556 AATGGAGA GGCTAGCTACAACGA CTGTAATC 4842

675 AGAUCUCC A UUUAUUGC 3557 GCAATAAA GGCTAGCTACAACGA GGAGATCT 4843

679 CUCCAUUU A UUGCUUCU 3558 AGAAGCAA GGCTAGCTACAACGA AAATGGAG 4844

682 CAUUUAUU G CUUCUGUU 3559 AACAGAAG GGCTAGCTACAACGA AATAAATG 4845 688 UUGCUUCU G UUAGUGAC 3560 GTCACTAA GGCTAGCTACAACGA AGAAGCAA 4846

692 UUCUGUUA G UGACCAAC 3561 GTTGGTCA GGCTAGCTACAACGA TAACAGAA 4847

695 UGUUAGUG A CCAACAUG 3562 CATGTTGG GGCTAGCTACAACGA CACTAACA 4848

699 AGUGACCA A CAUGGAGU 3563 ACTCCATG GGCTAGCTACAACGA TGGTCACT 4849

701 UGACCAAC A UGGAGUCG 3564 CGACTCCA GGCTAGCTACAACGA GTTGGTCA 4850

706 AACAUGGA G UCGUGUAC 3565 GTACACGA GGCTAGCTACAACGA TCCATGTT 4851

709 AUGGAGUC G UGUACAUU 3566 AATGTACA GGCTAGCTACAACGA GACTCCAT 4852

711 GGAGUCGU G UACAUUAC 3567 GTAATGTA GGCTAGCTACAACGA ACGACTCC 4853

713 AGUCGUGU A CAUUACUG 3568 CAGTAATG GGCTAGCTACAACGA ACACGACT 4854

715 UCGUGUAC A UUACUGAG 3569 CTCAGTAA GGCTAGCTACAACGA GTACACGA 4855

718 UGUACAUU A CUGAGAAC 3570 GTTCTCAG GGCTAGCTACAACGA AATGTACA 4856

725 UACUGAGA A CAAAAACA 3571 TGTTTTTG GGCTAGCTACAACGA TCTCAGTA 4857

731 GAACAAAA A CAAAACUG 3572 CAGTTTTG GGCTAGCTACAACGA TTTTGTTC 4858

736 AAAACAAA A CUGUGGUG 3573 CACCACAG GGCTAGCTACAACGA TTTGTTTT 4859

739 ACAAAACU G UGGUGAUU 3574 AATCACCA GGCTAGCTACAACGA AGTTTTGT 4860

742 AAACUGUG G UGAUUCCA 3575 TGGAATCA GGCTAGCTACAACGA CACAGTTT 4861

745 CUGUGGUG A UUCCAUGU 3576 ACATGGAA GGCTAGCTACAACGA CACCACAG 4862

750 GUGAUUCC A UGUCUCGG 3577 CCGAGACA GGCTAGCTACAACGA GGAATCAC 4863

752 GAUUCCAU G UCUCGGGU 3578 ACCCGAGA GGCTAGCTACAACGA ATGGAATC 4864

759 UGUCUCGG G UCCAUUUC 3579 GAAATGGA GGCTAGCTACAACGA CCGAGACA 4865

763 UCGGGUCC A UUUCAAAU 3580 ATTTGAAA GGCTAGCTACAACGA GGACCCGA 4866

770 CAUUUCAA A UCUCAACG 3581 CGTTGAGA GGCTAGCTACAACGA TTGAAATG 4867

776 AAAUCUCA A CGUGUCAC 3582 GTGACACG GGCTAGCTACAACGA TGAGATTT 4868

778 AUCUCAAC G UGUCACUU 3583 AAGTGACA GGCTAGCTACAACGA GTTGAGAT 4869

780 CUCAACGU G UCACUUUG 3584 CAAAGTGA GGCTAGCTACAACGA ACGTTGAG 4870

783 AACGUGUC A CUUUGUGC 3585 GCACAAAG GGCTAGCTACAACGA GACACGTT 4871

788 GUCACUUU G UGCAAGAU 3586 ATCTTGCA GGCTAGCTACAACGA AAAGTGAC 4872

790 CACUUUGU G CAAGAUAC 3587 GTATCTTG GGCTAGCTACAACGA ACAAAGTG 4873

795 UGUGCAAG A UACCCAGA 3588 TCTGGGTA GGCTAGCTACAACGA CTTGCACA 4874

797 UGCAAGAU A CCCAGAAA 3589 TTTCTGGG GGCTAGCTACAACGA ATCTTGCA 4875

810 GAAAAGAG A UUUGUUCC 3590 GGAACAAA GGCTAGCTACAACGA CTCTTTTC 4876

814 AGAGAUUU G UUCCUGAU 3591 ATCAGGAA GGCTAGCTACAACGA AAATCTCT 4877

821 UGUUCCUG A UGGUAACA 3592 TGTTACCA GGCTAGCTACAACGA CAGGAACA 4878

824 UCCUGAUG G UAACAGAA 3593 TTCTGTTA GGCTAGCTACAACGA CATCAGGA 4879

827 UGAUGGUA A CAGAAUUU 3594 AAATTCTG GGCTAGCTACAACGA TACCATCA 4880

832 GUAACAGA A UUUCCUGG 3595 CCAGGAAA GGCTAGCTACAACGA TCTGTTAC 4881

842 UUCCUGGG A CAGCAAGA 3596 TCTTGCTG GGCTAGCTACAACGA CCCAGGAA 4882

845 CUGGGACA G CAAGAAGG 3597 CCTTCTTG GGCTAGCTACAACGA TGTCCCAG 4883

854 CAAGAAGG G CUUUACUA 3598 TAGTAAAG GGCTAGCTACAACGA CCTTCTTG 4884

859 AGGGCUUU A CUAUUCCC 3599 GGGAATAG GGCTAGCTACAACGA AAAGCCCT 4885

862 GCUUUACU A UUCCCAGC 3600 GCTGGGAA GGCTAGCTACAACGA AGTAAAGC 4886

869 UAUUCCCA G CUACAUGA 3601 TCATGTAG GGCTAGCTACAACGA TGGGAATA 4887

872 UCCCAGCU A CAUGAUCA 3602 TGATCATG GGCTAGCTACAACGA AGCTGGGA 4888

874 CCAGCUAC A UGAUCAGC 3603 GCTGATCA GGCTAGCTACAACGA GTAGCTGG 4889

877 GCUACAUG A UCAGCUAU 3604 ATAGCTGA GGCTAGCTACAACGA CATGTAGC 4890

881 CAUGAUCA G CUAUGCUG 3605 CAGCATAG GGCTAGCTACAACGA TGATCATG 4891

884 GAUCAGCU A UGCUGGCA 3606 TGCCAGCA GGCTAGCTACAACGA AGCTGATC 4892

886 UCAGCUAU G CUGGCAUG 3607 CATGCCAG GGCTAGCTACAACGA ATAGCTGA 4893

890 CUAUGCUG G CAUGGUCU 3608 AGACCATG GGCTAGCTACAACGA CAGCATAG 4894

892 AUGCUGGC A UGGUCUUC 3609 GAAGACCA GGCTAGCTACAACGA GCCAGCAT 4895

895 CUGGCAUG G UCUUCUGU 3610 ACAGAAGA GGCTAGCTACAACGA CATGCCAG 4896

902 GGUCUUCU G UGAAGCAA 3611 TTGCTTCA GGCTAGCTACAACGA AGAAGACC 4897

907 UCUGUGAA G CAAAAAUU 3612 AATTTTTG GGCTAGCTACAACGA TTCACAGA 4898 913 AAGCAAAA A UUAAUGAU 3613 ATCATTAA GGCTAGCTACAACGA TTTTGCTT 4899

917 AAAAAUUA A UGAUGAAA 3614 TTTCATCA GGCTAGCTACAACGA TAATTTTT 4900

920 AAUUAAUG A UGAAAGUU 3615 AACTTTCA GGCTAGCTACAACGA CATTAATT 4901

926 UGAUGAAA G UUACCAGU 3616 ACTGGTAA GGCTAGCTACAACGA TTTCATCA 4902

929 UGAAAGUU A CCAGUCUA 3617 TAGACTGG GGCTAGCTACAACGA AACTTTCA 4903

933 AGUUACCA G UCUAUUAU 3618 ATAATAGA GGCTAGCTACAACGA TGGTAACT 4904

937 ACCAGUCU A UUAUGUAC 3619 GTACATAA GGCTAGCTACAACGA AGACTGGT 4905

940 AGUCUAUU A UGUACAUA 3620 TATGTACA GGCTAGCTACAACGA AATAGACT 4906

942 UCUAUUAU G UACAUAGU 3621 ACTATGTA GGCTAGCTACAACGA ATAATAGA 4907

944 UAUUAUGU A CAUAGUUG 3622 CAACTATG GGCTAGCTACAACGA ACATAATA 4908

946 UUAUGUAC A UAGUUGUC 3623 GACAACTA GGCTAGCTACAACGA GTACATAA 4909

949 UGUACAUA G UUGUCGUU 3624 AACGACAA GGCTAGCTACAACGA TATGTACA 4910

952 ACAUAGUU G UCGUUGUA 3625 TACAACGA GGCTAGCTACAACGA AACTATGT 4911

955 UAGUUGUC G UUGUAGGG 3626 CCCTACAA GGCTAGCTACAACGA GACAACTA 4912

958 UUGUCGUU G UAGGGUAU 3627 ATACCCTA GGCTAGCTACAACGA AACGACAA 4913

963 GUUGUAGG G UAUAGGAU 3628 ATCCTATA GGCTAGCTACAACGA CCTACAAC 4914

965 UGUAGGGU A UAGGAUUU 3629 AAATCCTA GGCTAGCTACAACGA ACCCTACA 4915

970 GGUAUAGG A UUUAUGAU 3630 ATCATAAA GGCTAGCTACAACGA CCTATACC 4916

974 UAGGAUUU A UGAUGUGG 3631 CCACATCA GGCTAGCTACAACGA AAATCCTA 4917

977 GAUUUAUG A UGUGGUUC 3632 GAACCACA GGCTAGCTACAACGA CATAAATC 4918

979 UUUAUGAU G UGGUUCUG 3633 CAGAACCA GGCTAGCTACAACGA ATCATAAA 4919

982 AUGAUGUG G UUCUGAGU 3634 ACTCAGAA GGCTAGCTACAACGA CACATCAT 4920

989 GGUUCUGA G UCCGUCUC 3635 GAGACGGA GGCTAGCTACAACGA TCAGAACC 4921

993 CUGAGUCC G UCUCAUGG 3636 CCATGAGA GGCTAGCTACAACGA GGACTCAG 4922

998 UCCGUCUC A UGGAAUUG 3637 CAATTCCA GGCTAGCTACAACGA GAGACGGA 4923

1003 CUCAUGGA A UUGAACUA 3638 TAGTTCAA GGCTAGCTACAACGA TCCATGAG 4924

1008 GGAAUUGA A CUAUCUGU 3639 ACAGATAG GGCTAGCTACAACGA' TCAATTCC 4925

1011 AUUGAACU A UCUGUUGG 3640 CCAACAGA GGCTAGCTACAACGA AGTTCAAT 4926

1015¹ AACUAUCU G UUGGAGAA 3641 TTCTCCAA GGCTAGCTACAACGA AGATAGTT 4927

1026 GGAGAAAA G CUUGUCUU 3642 AAGACAAG GGCTAGCTACAACGA TTTTCTCC 4928

1030 AAAAGCUU G UCUUAAAU 3643 ATTTAAGA GGCTAGCTACAACGA AAGCTTTT 4929

1037 UGUCUUAA A UUGUACAG 3644 CTGTACAA GGCTAGCTACAACGA TTAAGACA 4930

1040 CUUAAAUU G UACAGCAA 3645 TTGCTGTA GGCTAGCTACAACGA AATTTAAG 4931

1042 UAAAUUGU A CAGCAAGA 3646 TCTTGCTG GGCTAGCTACAACGA ACAATTTA 4932

1045 AUUGUACA G CAAGAACU 3647 AGTTCTTG GGCTAGCTACAACGA TGTACAAT 4933

1051 CAGCAAGA A CUGAACUA 3648 TAGTTCAG GGCTAGCTACAACGA TCTTGCTG 4934

1056 AGAACUGA A CUAAAUGU 3649 ACATTTAG GGCTAGCTACAACGA TCAGTTCT 4935

1061 UGAACUAA A UGUGGGGA 3650 TCCCCACA GGCTAGCTACAACGA TTAGTTCA 4936

1063 AACUAAAU G UGGGGAUU 3651 AATCCCCA GGCTAGCTACAACGA ATTTAGTT 4937

1069 AUGUGGGG A UUGACUUC 3652 GAAGTCAA GGCTAGCTACAACGA CCCCACAT 4938

1073 GGGGAUUG A CUUCAACU 3653 AGTTGAAG GGCTAGCTACAACGA CAATCCCC 4939

1079 UGACUUCA A CUGGGAAU 3654 ATTCCCAG GGCTAGCTACAACGA TGAAGTCA 4940

1086 AACUGGGA A UACCCUUC 3655 GAAGGGTA GGCTAGCTACAACGA TCCCAGTT 4941

1088 CUGGGAAU A CCCUUCUU 3656 AAGAAGGG GGCTAGCTACAACGA ATTCCCAG 4942

1101 UCUUCGAA G CAUCAGCA 3657 TGCTGATG GGCTAGCTACAACGA TTCGAAGA 4943

1103 UUCGAAGC A UCAGCAUA 3658 TATGCTGA GGCTAGCTACAACGA GCTTCGAA 4944

1107 AAGCAUCA G CAUAAGAA 3659 TTCTTATG GGCTAGCTACAACGA TGATGCTT 4945

1109 GCAUCAGC A UAAGAAAC 3660 GTTTCTTA GGCTAGCTACAACGA GCTGATGC 4946

1116 CAUAAGAA A CUUGUAAA 3661 TTTACAAG GGCTAGCTACAACGA TTCTTATG 4947

1120 AGAAACUU G UAAACCGA 3662 TCGGTTTA GGCTAGCTACAACGA AAGTTTCT 4948

1124 ACUUGUAA A CCGAGACC 3663 GGTCTCGG GGCTAGCTACAACGA TTACAAGT 4949

1130 AAACCGAG A CCUAAAAA 3664 TTTTTAGG GGCTAGCTACAACGA CTCGGTTT 4950

1138 ACCUAAAA A CCCAGUCU 3665 AGACTGGG GGCTAGCTACAACGA TTTTAGGT 4951 1143 AAAACCCA G UCUGGGAG 3666 CTCCCAGA GGCTAGCTACAACGA TGGGTTTT 4952

1151 GUCUGGGA G UGAGAUGA 3667 TCATCTCA GGCTAGCTACAACGA TCCCAGAC 4953

1156 GGAGUGAG A UGAAGAAA 3668 TTTCTTCA GGCTAGCTACAACGA CTCACTCC 4954

1164 AUGAAGAA A UUUUUGAG 3669 CTCAAAAA GGCTAGCTACAACGA TTCTTCAT 4955

1172 AUUUUUGA G CACCUUAA 3670 TTAAGGTG GGCTAGCTACAACGA TCAAAAAT 4956

1174 UUUUGAGC A CCUUAACU 3671 AGTTAAGG GGCTAGCTACAACGA GCTCAAAA 4957

1180 GCACCUUA A CUAUAGAU 3672 ATCTATAG GGCTAGCTACAACGA TAAGGTGC 4958

1183 CCUUAACU A UAGAUGGU 3673 ACCATCTA GGCTAGCTACAACGA AGTTAAGG 4959

1187 AACUAUAG A UGGUGUAA 3674 TTACACCA GGCTAGCTACAACGA CTATAGTT 4960

1190 UAUAGAUG G UGUAACCC 3675 GGGTTACA GGCTAGCTACAACGA CATCTATA 4961

1192 UAGAUGGU G UAACCCGG 3676 CCGGGTTA GGCTAGCTACAACGA ACCATCTA 4962

1195 AUGGUGUA A CCCGGAGU 3677 ACTCCGGG GGCTAGCTACAACGA TACACCAT 4963

1202 AACCCGGA G UGACCAAG 3678 GTTGGTCA GGCTAGCTACAACGA TCCGGGTT 4964

1205 CCGGAGUG A CCAAGGAU 3679 ATCCTTGG GGCTAGCTACAACGA CACTCCGG 4965

1212 GACCAAGG A UUGUACAC 3680 GTGTACAA GGCTAGCTACAACGA CCTTGGTC 4966

1215 CAAGGAUU G UACACCUG 3681 CAGGTGTA GGCTAGCTACAACGA AATCCTTG 4967

1217 AGGAUUGU A CACCUGUG 3682 CACAGGTG GGCTAGCTACAACGA ACAATCCT 4968

1219 GAUUGUAC A CCUGUGCA 3683 TGCACAGG GGCTAGCTACAACGA GTACAATC 4969

1223 GUACACCU G UGCAGCAU 3684 ATGCTGCA GGCTAGCTACAACGA AGGTGTAC 4970

1225 ACACCUGU G CAGCAUCC 3685 GGATGCTG GGCTAGCTACAACGA ACAGGTGT 4971

1228 CCUGUGCA G CAUCCAGU 3686 ACTGGATG GGCTAGCTACAACGA TGCACAGG 4972

1230 UGUGCAGC A UCCAGUGG 3687 CCACTGGA GGCTAGCTACAACGA GCTGCACA 4973

1235 AGCAUCCA G UGGGCUGA 3688 TCAGCCCA GGCTAGCTACAACGA TGGATGCT 4974

1239 UCCAGUGG G CUGAUGAC 3689 GTCATCAG GGCTAGCTACAACGA CCACTGGA 4975

1243 GUGGGCUG A UGACCAAG 3690 CTTGGTCA GGCTAGCTACAACGA CAGCCCAC 4976

1246 GGCUGAUG A CCAAGAAG 3691 CTTCTTGG GGCTAGCTACAACGA CATCAGCC 4977

1256 CAAGAAGA A CAGCACAU 3692 ATGTGCTG GGCTAGCTACAACGA TCTTGTTG 4978

1259 GAAGAACA G CACAUUUG 3693 CAAATGTG GGCTAGCTACAACGA TGTTCTTC 4979

1261 AGAACAGC A CAUUUGUC 3694 GACAAATG GGCTAGCTACAACGA GCTGTTCT 4980

1263 AACAGCAC A UUUGUCAG 3695 CTGACAAA GGCTAGCTACAACGA GTGCTGTT 4981

1267 GCACAUUU G UCAGGGUC 3696 GACCCTGA GGCTAGCTACAACGA AAATGTGC 4982

1273 UUGUCAGG G UCCAUGAA 3697 TTCATGGA GGCTAGCTACAACGA CCTGACAA 4983

1277 CAGGGUCC A UGAAAAAC 3698 GTTTTTCA GGCTAGCTACAACGA GGACCCTG 4984

1284 CAUGAAAA A CCUUUUGU 3699 ACAAAAGG GGCTAGCTACAACGA TTTTCATG 4985

1291 AACCUUUU G UUGCUUUU 3700 AAAAGCAA GGCTAGCTACAACGA AAAAGGTT 4986

1294 CUUUUGUU G CUUUUGGA 3701 TCCAAAAG GGCTAGCTACAACGA AACAAAAG 4987

1304 UUUUGGAA G UGGCAUGG 3702 CCATGCCA GGCTAGCTACAACGA TTCCAAAA 4988

1307 UGGAAGUG G CAUGGAAU 3703 ATTCCATG GGCTAGCTACAACGA CACTTCCA 4989

1309 GAAGUGGC A UGGAAUCU 3704 AGATTCCA GGCTAGCTACAACGA GCCACTTC 4990

1314 GGCAUGGA A UCUCUGGU 3705 ACCAGAGA GGCTAGCTACAACGA TCCATGCC 4991

1321 AAUCUCUG G UGGAAGCC 3706 GGCTTCCA GGCTAGCTACAACGA CAGAGATT 4992

1327 UGGUGGAA G CCACGGUG 3707 CACCGTGG GGCTAGCTACAACGA TTCCACCA 4993

1330 UGGAAGCC A CGGUGGGG 3708 CCCCACCG GGCTAGCTACAACGA GGCTTCCA 4994

1333 AAGCCACG G UGGGGGAG 3709 CTCCCCCA GGCTAGCTACAACGA CGTGGCTT 4995

1341 GUGGGGGA G CGUGUCAG 3710 CTGACACG GGCTAGCTACAACGA TCCCCCAC 4996

1343 GGGGGAGC G UGUCAGAA 3711 TTCTGACA GGCTAGCTACAACGA GCTCCCCC 4997

1345 GGGAGCGU G UCAGAAUC 3712 GATTCTGA GGCTAGCTACAACGA ACGCTCCC 4998

1351 GUGUCAGA A UCCCUGCG 3713 CGCAGGGA GGCTAGCTACAACGA TCTGACAC 4999

1357 GAAUCCCU G CGAAGUAC 3714 GTACTTCG GGCTAGCTACAACGA AGGGATTC 5000

1362 CCUGCGAA G UACCUUGG 3715 CCAAGGTA GGCTAGCTACAACGA TTCGCAGG 5001

1364 UGCGAAGU A CCUUGGUU 3716 AACCAAGG GGCTAGCTACAACGA ACTTCGCA 5002

1370 GUACCUUG G UUACCCAC 3717 GTGGGTAA GGCTAGCTACAACGA CAAGGTAC 5003

1373 CCUUGGUU A CCCACCCC 3718 GGGGTGGG GGCTAGCTACAACGA AACCAAGG 5004 1377 GGUUACCC A CCCCCAGA 3719 TCTGGGGG GGCTAGCTACAACGA GGGTAACC 5005

1387 CCCCAGAA A UAAAAUGG 3720 CCATTTTA GGCTAGCTACAACGA TTCTGGGG 5006

1392 GAAAUAAA A UGGUAUAA 3721 TTATACCA GGCTAGCTACAACGA TTTATTTC 5007

1395 AUAAAAUG G UAUAAAAA 3722 TTTTTATA GGCTAGCTACAACGA CATTTTAT 5008

1397 AAAAUGGU A UAAAAAUG 3723 CATTTTTA GGCTAGCTACAACGA ACCATTTT 5009

1403 GUAUAAAA A UGGAAUAC 3724 GTATTCCA GGCTAGCTACAACGA TTTTATAC 5010

1408 AAAAUGGA A UACCCCUU 3725 AAGGGGTA GGCTAGCTACAACGA TCCATTTT 5011

1410 AAUGGAAU A CCCCUUGA 3726 TCAAGGGG GGCTAGCTACAACGA ATTCCATT 5012

1419 CCCCUUGA G UCCAAUCA 3727 TGATTGGA GGCTAGCTACAACGA TCAAGGGG 5013

1424 UGAGUCCA A UCACACAA 3728 TTGTGTGA GGCTAGCTACAACGA TGGACTCA 5014

1427 GUCCAAUC A CACAAUUA 3729 TAATTGTG GGCTAGCTACAACGA GATTGGAC 5015

1429 CCAAUCAC A CAAUUAAA 3730 TTTAATTG GGCTAGCTACAACGA GTGATTGG 5016

1432 AUCACACA A UUAAAGCG 3731 CGCTTTAA GGCTAGCTACAACGA TGTGTGAT 5017

1438 CAAUUAAA G CGGGGCAU 3732 ATGCCCCG GGCTAGCTACAACGA TTTAATTG 5018

1443 AAAGCGGG G CAUGUACU 3733 AGTACATG GGCTAGCTACAACGA CCCGCTTT 5019

1445 AGCGGGGC A UGUACUGA 3734 TCAGTACA GGCTAGCTACAACGA GCCCCGCT 5020

1447 CGGGGCAU G UACUGACG 3735 CGTCAGTA GGCTAGCTACAACGA ATGCCCCG 5021

1449 GGGCAUGU A CUGACGAU 3736 ATCGTCAG GGCTAGCTACAACGA ACATGCCC 5022

1453 AUGUACUG A CGAUUAUG 3737 CATAATCG GGCTAGCTACAACGA CAGTACAT 5023

1456 UACUGACG A UUAUGGAA 3738 TTCCATAA GGCTAGCTACAACGA CGTCAGTA 5024

1459 UGACGAUU A UGGAAGUG 3739 CACTTCCA GGCTAGCTACAACGA AATCGTCA 5025

1465 UUAUGGAA G UGAGUGAA 3740 TTCACTCA GGCTAGCTACAACGA TTCCATAA 5026

1469 GGAAGUGA G UGAAAGAG 3741 CTCTTTCA GGCTAGCTACAACGA TCACTTCC 5027

1478 UGAAAGAG A CACAGGAA 3742 TTCCTGTG GGCTAGCTACAACGA CTCTTTCA 5028

1480 AAAGAGAC A CAGGAAAU 3743 ATTTCCTG GGCTAGCTACAACGA GTCTCTTT 5029

1487 CACAGGAA A UUACACUG 3744 CAGTGTAA GGCTAGCTACAACGA TTCCTGTG 5030

1490 AGGAAAUU A CACUGUCA 3745 TGACAGTG GGCTAGCTACAACGA AATTTCCT 5031

1492 GAAAUUAC A CUGUCAUC 3746 GATGACAG GGCTAGCTACAACGA GTAATTTC 5032

1495 AUUACACU G UCAUCCUU 3747 AAGGATGA GGCTAGCTACAACGA AGTGTAAT 5033

1498 ACACUGUC A UCCUUACC 3748 GGTAAGGA GGCTAGCTACAACGA GACAGTGT 5034

1504 UCAUCCUU A CCAAUCCC 3749 GGGATTGG GGCTAGCTACAACGA AAGGATGA 5035

1508 CCUUACCA A UCCCAUUU 3750 AAATGGGA GGCTAGCTACAACGA TGGTAAGG 5036

1513 CCAAUCCC A UUUCAAAG 3751 CTTTGAAA GGCTAGCTACAACGA GGGATTGG 5037

1527 AAGGAGAA G CAGAGCCA 3752 TGGCTCTG GGCTAGCTACAACGA TTCTCCTT 5038

1532 GAAGCAGA G CCAUGUGG 3753 CCACATGG GGCTAGCTACAACGA TCTGCTTC 5039

1535 GCAGAGCC A UGUGGUCU 3754 AGACCACA GGCTAGCTACAACGA GGCTCTGC 5040

1537 AGAGCCAU G UGGUCUCU 3755 AGAGACCA GGCTAGCTACAACGA ATGGCTCT 5041

1540 GCCAUGUG G UCUCUCUG 3756 CAGAGAGA GGCTAGCTACAACGA CACATGGC 5042

1549 UCUCUCUG G UUGUGUAU 3757 ATACACAA GGCTAGCTACAACGA CAGAGAGA 5043

1552 CUCUGGUU G UGUAUGUC 3758 GACATACA GGCTAGCTACAACGA AACCAGAG 5044

1554 CUGGUUGU G UAUGUCCC 3759 GGGACATA GGCTAGCTACAACGA ACAACCAG 5045

1556 GGUUGUGU A UGUCCCAC 3760 GTGGGACA GGCTAGCTACAACGA ACACAACC 5046

1558 UUGUGUAU G UCCCACCC 3761 GGGTGGGA GGCTAGCTACAACGA ATACACAA 5047

1563 UAUGUCCC A CCCCAGAU 3762 ATCTGGGG GGCTAGCTACAACGA GGGACATA 5048

1570 CACCCCAG A UUGGUGAG 3763 CTCACCAA GGCTAGCTACAACGA CTGGGGTG 5049

1574 CCAGAUUG G UGAGAAAU 3764 ATTTCTCA GGCTAGCTACAACGA CAATCTGG 5050

1581 GGUGAGAA A UCUCUAAU 3765 ATTAGAGA GGCTAGCTACAACGA TTCTCACC 5051

1588 AAUCUCUA A UCUCUCCU 3766 AGGAGAGA GGCTAGCTACAACGA TAGAGATT 5052

1597 UCUCUCCU G UGGAUUCC 3767 GGAATCCA GGCTAGCTACAACGA AGGAGAGA 5053

1601 UCCUGUGG A UUCCUACC 3768 GGTAGGAA GGCTAGCTACAACGA CCACAGGA 5054

1607 GGAUUCCU A CCAGUACG 3769 CGTACTGG GGCTAGCTACAACGA AGGAATCC 5055

1611 UCCUACCA G UACGGCAC 3770 GTGCCGTA GGCTAGCTACAACGA TGGTAGGA 5056

1613 CUACCAGU A CGGCACCA 3771 TGGTGCCG GGCTAGCTACAACGA ACTGGTAG 5057 1616 CCAGUACG G CACCACUC 3772 GAGTGGTG GGCTAGCTACAACGA CGTACTGG 5058

1618 AGUACGGC A CCACUCAA 3773 TTGAGTGG GGCTAGCTACAACGA GCCGTACT 5059

1621 ACGGCACC A CUCAAACG 3774 CGTTTGAG GGCTAGCTACAACGA GGTGCCGT 5060

1627 CCACUCAA A CGCUGACA 3775 TGTCAGCG GGCTAGCTACAACGA TTGAGTGG 5061

1629 ACUCAAAC G CUGACAUG 3776 CATGTCAG GGCTAGCTACAACGA GTTTGAGT 5062

1633 AAACGCUG A CAUGUACG 3777 CGTACATG GGCTAGCTACAACGA CAGCGTTT 5063

1635 ACGCUGAC A UGUACGGU 3778 ACCGTACA GGCTAGCTACAACGA GTCAGCGT 5064

1637 GCUGACAU G UACGGUCU 3779 AGACCGTA GGCTAGCTACAACGA ATGTCAGC 5065

1639 UGACAUGU A CGGUCUAU 3780 ATAGACCG GGCTAGCTACAACGA ACATGTCA 5066

1642 CAUGUACG G UCUAUGCC 3781 GGCATAGA GGCTAGCTACAACGA CGTACATG 5067

1646 UAGGGUCU A UGCCAUUC 3782 GAATGGCA GGCTAGCTACAACGA AGACCGTA 5068

1648 CGGUCUAU G CCAUUCCU 3783 AGGAATGG GGCTAGCTACAACGA ATAGACCG 5069

1651 UCUAUGCC A UUCCUCCC 3784 GGGAGGAA GGCTAGCTACAACGA GGCATAGA 5070

1662 CCUCCCCC G CAUCACAU 3785 ATGTGATG GGCTAGCTACAACGA GGGGGAGG 5071

1664 UCCCCCGC A UCACAUCC 3786 GGATGTGA GGCTAGCTACAACGA GCGGGGGA 5072

1667 CCCGCAUC A CAUCCACU 3787 AGTGGATG GGCTAGCTACAACGA GATGCGGG 5073

1669 CGCAUCAC A UCCACUGG 3788 CCAGTGGA GGCTAGCTACAACGA GTGATGCG 5074

1673 UCACAUCC A CUGGUAUU 3789 AATACCAG GGCTAGCTACAACGA GGATGTGA 5075

1677 AUCCACUG G UAUUGGCA 3790 TGCCAATA GGCTAGCTACAACGA CAGTGGAT 5076

1679 CCACUGGU A UUGGCAGU 3791 ACTGGCAA GGCTAGCTACAACGA ACCAGTGG 5077

1683 UGGUAUUG G CAGUUGGA 3792 TCCAACTG GGCTAGCTACAACGA CAATACCA 5078

1686 UAUUGGCA G UUGGAGGA 3793 TCCTCCAA GGCTAGCTACAACGA TGCCAATA 5079

1698 GAGGAAGA G UGCGCCAA 3794 TTGGCGCA GGCTAGCTACAACGA TCTTCCTC 5080

1700 GGAAGAGU G CGCCAACG 3795 CGTTGGCG GGCTAGCTACAACGA ACTCTTCC 5081

1702 AAGAGUGC G CCAACGAG 3796 CTCGTTGG GGCTAGCTACAACGA GCACTCTT 5082

1706 GUGCGCCA A CGAGCCCA 3797 TGGGCTCG GGCTAGCTACAACGA TGGCGCAC 5083

1710 GCCAACGA G CGCAGCCA 3798 TGGCTGGG GGCTAGCTACAACGA TCGTTGGC 5084

1715 CGAGCCCA G CCAAGCUG 3799 CAGCTTGG GGCTAGCTACAACGA TGGGCTCG 5085

1720 CCAGCCAA G CUGUCUCA 3800 TGAGACAG GGCTAGCTACAACGA TTGGCTGG 5086

1723 GCCAAGCU G UCUCAGUG 3801 CACTGAGA GGCTAGCTACAACGA AGCTTGGC 5087

1729 CUGUCUCA G UGACAAAC 3802 GTTTGTCA GGCTAGCTACAACGA TGAGACAG 5088

1732 UCUCAGUG A CAAACCCA 3803 TGGGTTTG GGCTAGCTACAACGA CACTGAGA 5089

1736 AGUGACAA A CCCAUACC 3804 GGTATGGG GGCTAGCTACAACGA TTGTCACT 5090

1740 ACAAACCC A UACCCUUG 3805 CAAGGGTA GGCTAGCTACAACGA GGGTTTGT 5091

1742 AAACCCAU A CCCUUGUG 3806 CACAAGGG GGCTAGCTACAACGA ATGGGTTT 5092

1748 AUACCCUU G UGAAGAAU 3807 ATTCTTCA GGCTAGCTACAACGA AAGGGTAT 5093

1755 UGUGAAGA A UGGAGAAG 3808 CTTCTCCA GGCTAGCTACAACGA TCTTCACA 5094

1763 AUGGAGAA G UGUGGAGG 3809 CCTCCACA GGCTAGCTACAACGA TTCTCCAT 5095

1765 GGAGAAGU G UGGAGGAC 3810 GTCCTCCA GGCTAGCTACAACGA ACTTCTCC 5096

1772 UGUGGAGG A CUUCCAGG 3811 CCTGGAAG GGCTAGCTACAACGA CCTCCACA 5097

1787 GGGAGGAA A UAAAAUUG 3812 CAATTTTA GGCTAGCTACAACGA TTCCTCCC 5098

1792 GAAAUAAA A UUGAAGUU 3813 AACTTCAA GGCTAGCTACAACGA TTTATTTC 5099

1798 AAAUUGAA G UUAAUAAA 3814 TTTATTAA GGCTAGCTACAACGA TTCAATTT 5100

1802 UGAAGUUA A UAAAAAUC 3815 GATTTTTA GGCTAGCTACAACGA TAACTTCA 5101

1808 UAAUAAAA A UCAAUUUG 3816 CAAATTGA GGCTAGCTACAACGA TTTTATTA 5102

1812 AAAAAUCA A UUUGCUCU 3817 AGAGCAAA GGCTAGCTACAACGA TGATTTTT 5103

1816 AUCAAUUU G CUCUAAUU 3818 AATTAGAG GGCTAGCTACAACGA AAATTGAT 5104

1822 UUGCUCUA A UUGAAGGA 3819 TCCTTGAA GGCTAGCTACAACGA TAGAGCAA 5105

1835 AGGAAAAA A CAAAACUG 3820 CAGTTTTG GGCTAGCTACAACGA TTTTTCCT 5106

1840 AAAACAAA A CUGUAAGU 3821 ACTTACAG GGCTAGCTACAACGA TTTGTTTT 5107

1843 ACAAAACU G UAAGUACC 3822 GGTACTTA GGCTAGCTACAACGA AGTTTTGT 5108

1847 AACUGUAA G UACCCUUG 3823 CAAGGGTA GGCTAGCTACAACGA TTACAGTT 5109

1849 CUGUAAGU A CCCUUGUU 3824 AACAAGGG GGCTAGCTACAACGA ACTTACAG 5110 1855 GUACCCUU G UUAUCCAA 3825 TTGGATAA GGCTAGCTACAACGA AAGGGTAC 5111

1858 CCCUUGUU A UCCAAGCG 3826 CGCTTGGA GGCTAGCTACAACGA AACAAGGG 5112

1864 UUAUCCAA G CGGCAAAU 3827 ATTTGCCG GGCTAGCTACAACGA TTGGATAA 5113

1867 UCCAAGCG G CAAAUGUG 3828 CACATTTG GGCTAGCTACAACGA CGCTTGGA 5114

1871 AGCGGCAA A UGUGUCAG 3829 CTGACACA GGCTAGCTACAACGA TTGCCGCT 5115

1873 CGGCAAAU G UGUCAGCU 3830 AGCTGACA GGCTAGCTACAACGA ATTTGCCG 5116

1875 GCAAAUGU G UCAGCUUU 3831 AAAGCTGA GGCTAGCTACAACGA ACATTTGC 5117

1879 AUGUGUCA G CUUUGUAC 3832 GTACAAAG GGCTAGCTACAACGA TGACACAT 5118

1884 UCAGCUUU G UACAAAUG 3833 CATTTGTA GGCTAGCTACAACGA AAAGCTGA 5119

1886 AGCUUUGU A CAAAUGUG 3834 CACATTTG GGCTAGCTACAACGA ACAAAGCT 5120

1890 UUGUACAA A UGUGAAGC 3835 GCTTCACA GGCTAGCTACAACGA TTGTACAA 5121

1892 GUACAAAU G UGAAGCGG 3836 CCGCTTCA GGCTAGCTACAACGA ATTTGTAC 5122

1897 AAUGUGAA G CGGUCAAC 3837 GTTGACCG GGCTAGCTACAACGA TTCACATT 5123

1900 GUGAAGCG G UCAACAAA 3838 TTTGTTGA GGCTAGCTACAACGA CGCTTCAC 5124

1904 AGCGGUCA A CAAAGUCG 3839 CGACTTTG GGCTAGCTACAACGA TGACCGCT 5125

1909 UCAACAAA G UCGGGAGA 3840 TCTCCCGA GGCTAGCTACAACGA TTTGTTGA 5126

1927 GAGAGAGG G UGAUCUCC 3841 GGAGATCA GGCTAGCTACAACGA CCTCTCTC 5127

1930 AGAGGGUG A UCUCCUUC 3842 GAAGGAGA GGCTAGCTACAACGA CACCCTCT 5128

1940 CUCCUUCC A CGUGACCA 3843 TGGTCACG GGCTAGCTACAACGA GGAAGGAG 5129

1942 CCUUCCAC G UGACCAGG 3844 CCTGGTCA GGCTAGCTACAACGA GTGGAAGG 5130

1945 UCCACGUG A CCAGGGGU 3845 ACCCCTGG GGCTAGCTACAACGA CACGTGGA 5131

1952 GACCAGGG G UCCUGAAA 3846 TTTCAGGA GGCTAGCTACAACGA CCCTGGTC 5132

1960 GUCCUGAA A UUACUUUG 3847 CAAAGTAA GGCTAGCTACAACGA TTCAGGAC 5133

1963 CUGAAAUU A CUUUGCAA 3848 TTGCAAAG GGCTAGCTACAACGA AATTTCAG 5134

1968 AUUACUUU G CAACCUGA 3849 TCAGGTTG GGCTAGCTACAACGA AAAGTAAT 5135

1971 ACUUUGCA A CCUGACAU 3850 ATGTCAGG GGCTAGCTACAACGA TGCAAAGT 5136

1976 GCAACCUG A CAUGCAGC 3851 GCTGCATG GGCTAGCTACAACGA CAGGTTGC 5137

1978 AACCUGAC A UGCAGCCC 3852 GGGCTGCA GGCTAGCTACAACGA GTCAGGTT 5138

1980 CCUGACAU G CAGCCCAC 3853 GTGGGCTG GGCTAGCTACAACGA ATGTCAGG 5139

1983 GACAUGCA G CCCACUGA 3854 TCAGTGGG GGCTAGCTACAACGA TGCATGTC 5140

1987 UGCAGCCC A CUGAGCAG 3855 CTGCTCAG GGCTAGCTACAACGA GGGCTGCA 5141

1992 CCCACUGA G CAGGAGAG 3856 CTCTCCTG GGCTAGCTACAACGA TCAGTGGG 5142

2000 GCAGGAGA G CGUGUCUU 3857 AAGACACG GGCTAGCTACAACGA TCTCCTGC 5143

2002 AGGAGAGC G UGUCUUUG 3858 CAAAGACA GGCTAGCTACAACGA GCTCTCCT 5144

2004 GAGAGCGU G UCUUUGUG 3859 CACAAAGA GGCTAGCTACAACGA ACGCTCTC 5145

2010 GUGUCUUU G UGGUGCAC 3860 GTGCACCA GGCTAGCTACAACGA AAAGACAC 5146

2013 UCUUUGUG G UGCACUGC 3861 GCAGTGCA GGCTAGCTACAACGA CACAAAGA 5147

2015 UUUGUGGU G CACUGCAG 3862 CTGCAGTG GGCTAGCTACAACGA ACCACAAA 5148

2017 UGUGGUGC A CUGCAGAC 3863 GTCTGCAG GGCTAGCTACAACGA GCACCACA 5149

2020 GGUGCACU G CAGACAGA 3864 TCTGTCTG GGCTAGCTACAACGA AGTGCACC 5150

2024 CACUGCAG A CAGAUCUA 3865 TAGATCTG GGCTAGCTACAACGA CTGCAGTG 5151

2028 GCAGACAG A UCUACGUU 3866 AACGTAGA GGCTAGCTACAACGA CTGTCTGC 5152

2032 ACAGAUCU A CGUUUGAG 3867 CTCAAACG GGCTAGCTACAACGA AGATCTGT 5153

2034 AGAUCUAC G UUUGAGAA 3868 TTCTCAAA GGCTAGCTACAACGA GTAGATCT 5154

2042 GUUUGAGA A CCUCACAU 3869 ATGTGAGG GGCTAGCTACAACGA TCTCAAAC 5155

2047 AGAACCUC A CAUGGUAC 3870 GTACCATG GGCTAGCTACAACGA GAGGTTCT 5156

2049 AACCUCAC A UGGUACAA 3871 TTGTACCA GGCTAGCTACAACGA GTGAGGTT 5157

2052 CUCACAUG G UACAAGCU 3872 AGCTTGTA GGCTAGCTACAACGA CATGTGAG 5158

2054 CACAUGGU A CAAGCUUG 3873 CAAGCTTG GGCTAGCTACAACGA ACCATGTG 5159

2058 UGGUACAA G CUUGGCCC 3874 GGGCCAAG GGCTAGCTACAACGA TTGTACCA 5160

2063 CAAGCUUG G CCCACAGC 3875 GCTGTGGG GGCTAGCTACAACGA CAAGCTTG 5161

2067 CUUGGCCC A CAGCCUCU 3876 AGAGGCTG GGCTAGCTACAACGA GGGCCAAG 5162

2070 GGCCCACA G CCUCUGCC 3877 GGCAGAGG GGCTAGCTACAACGA TGTGGGCC 5163 2076 CAGCCUCU G CCAAUCCA 3878 TGGATTGG GGCTAGCTACAACGA AGAGGCTG 5164

2080 CUCUGCCA A UCCAUGUG 3879 CACATGGA GGCTAGCTACAACGA TGGCAGAG 5165

2084 GCCAAUCC A UGUGGGAG 3880 CTCCCACA GGCTAGCTACAACGA GGATTGGC 5166

2086 CAAUCCAU G UGGGAGAG 3881 CTCTCCCA GGCTAGCTACAACGA ATGGATTG 5167

2094 GUGGGAGA G UUGCCCAC 3882 GTGGGCAA GGCTAGCTACAACGA TCTCCCAC 5168

2097 GGAGAGUU G CCCACACC 3883 GGTGTGGG GGCTAGCTACAACGA AACTCTCC 5169

2101 AGUUGCCC A CACCUGUU 3884 AACAGGTG GGCTAGCTACAACGA GGGCAACT 5170

2103 UUGCCCAC A CCUGUUUG 3885 CAAACAGG GGCTAGCTACAACGA GTGGGCAA 5171

2107 CCACACCU G UUUGCAAG 3886 CTTGCAAA GGCTAGCTACAACGA AGGTGTGG 5172

2111 ACCUGUUU G CAAGAACU 3887 AGTTCTTG GGCTAGCTACAACGA AAACAGGT 5173

2117 UUGCAAGA A CUUGGAUA 3888 TATCCAAG GGCTAGCTACAACGA TCTTGCAA 5174

2123 GAACUUGG A UACUCUUU 3889 AAAGAGTA GGCTAGCTACAACGA CCAAGTTC 5175

2125 ACUUGGAU A CUCUUUGG 3890 CCAAAGAG GGCTAGCTACAACGA ATCCAAGT 5176

2136 CUUUGGAA A UUGAAUGC 3891 GCATTCAA GGCTAGCTACAACGA TTCCAAAG 5177

2141 GAAAUUGA A UGCCACCA 3892 TGGTGGCA GGCTAGCTACAACGA TCAATTTC 5178

2143 AAUUGAAU G CCACCAUG 3893 CATGGTGG GGCTAGCTACAACGA ATTCAATT 5179

2146 UGAAUGCC A CCAUGUUC 3894 GAAGATGG GGCTAGCTACAACGA GGCATTCA 5180

2149 AUGCCACC A UGUUCUCU 3895 AGAGAACA GGCTAGCTACAACGA GGTGGCAT 5181

2151 GCCACCAU G UUCUCUAA 3896 TTAGAGAA GGCTAGCTACAACGA ATGGTGGC 5182

2159 GUUCUCUA A UAGCACAA 3897 TTGTGCTA GGCTAGCTACAACGA TAGAGAAC 5183

2162 CUCUAAUA G CACAAAUG 3898 CATTTGTG GGCTAGCTACAACGA TATTAGAG 5184

2164 CUAAUAGC A CAAAUGAC 3899 GTCATTTG GGCTAGCTACAACGA GCTATTAG 5185

2168 UAGCACAA A UGACAUUU 3900 AAATGTCA GGCTAGCTACAACGA TTGTGCTA 5186

2171 CACAAAUG A CAUUUUGA 3901 TCAAAATG GGCTAGCTACAACGA CATTTGTG 5187

2173 CAAAUGAC A UUUUGAUC 3902 GATCAAAA GGCTAGCTACAACGA GTCATTTG 5188

2179 ACAUUUUG A UCAUGGAG 3903 CTCCATGA GGCTAGCTACAACGA CAAAATGT 5189

2182 UUUUGAUC A UGGAGCUU 3904 AAGCTCCA GGCTAGCTACAACGA GATCAAAA 5190

2187 AUCAUGGA G CUUAAGAA 3905 TTCTTAAG GGCTAGCTACAACGA TCCATGAT 5191

2195 GCUUAAGA A UGCAUCCU 3906 AGGATGCA GGCTAGCTACAACGA TCTTAAGC 5192

2197 UUAAGAAU G CAUCCUUG 3907 CAAGGATG GGCTAGCTACAACGA ATTCTTAA 5193

2199 AAGAAUGC A UCCUUGCA 3908 TGCAAGGA GGCTAGCTACAACGA GCATTCTT 5194

2205 GCAUCCUU G CAGGACCA 3909 TGGTCCTG GGCTAGCTACAACGA AAGGATGC 5195

2210 CUUGCAGG A CCAAGGAG 3910 CTCCTTGG GGCTAGCTACAACGA CCTGCAAG 5196

2219 CCAAGGAG A CUAUGUCU 3911 AGACATAG GGCTAGCTACAACGA CTCCTTGG 5197

2222 AGGAGACU A UGUCUGCC 3912 GGCAGACA GGCTAGCTACAACGA AGTCTCCT 5198

2224 GAGACUAU G UCUGCCUU 3913 AAGGCAGA GGCTAGCTACAACGA ATAGTCTC 5199

2228 CUAUGUCU G CCUUGCUC 3914 GAGCAAGG GGCTAGCTACAACGA AGACATAG 5200

2233 UCUGCCUU G CUCAAGAC 3915 GTCTTGAG GGCTAGCTACAACGA AAGGCAGA 5201

2240 UGCUCAAG A CAGGAAGA 3916 TCTTCCTG GGCTAGCTACAACGA CTTGAGCA 5202

2248 ACAGGAAG A CCAAGAAA 3917 TTTCTTGG GGCTAGCTACAACGA CTTCCTGT 5203

2259 AAGAAAAG A CAUUGCGU 3918 ACGCAATG GGCTAGCTACAACGA CTTTTCTT 5204

2261 GAAAAGAC A UUGCGUGG 3919 CCACGCAA GGCTAGCTACAACGA GTCTTTTC 5205

2264 AAGACAUU G CGUGGUCA 3920 TGACCACG GGCTAGCTACAACGA AATGTCTT 5206

2266 GACAUUGC G UGGUCAGG 3921 CCTGACCA GGCTAGCTACAACGA GCAATGTC 5207

2269 AUUGCGUG G UCAGGCAG 3922 CTGCCTGA GGCTAGCTACAACGA CACGCAAT 5208

2274 GUGGUCAG G CAGCUCAC 3923 GTGAGCTG GGCTAGCTACAACGA CTGACCAC 5209

2277 GUCAGGCA G CUCACAGU 3924 ACTGTGAG GGCTAGCTACAACGA TGCCTGAC 5210

2281 GGCAGCUC A CAGUCCUA 3925 TAGGACTG GGCTAGCTACAACGA GAGCTGCC 5211

2284 AGCUCACA G UCCUAGAG 3926 CTCTAGGA GGCTAGCTACAACGA TGTGAGCT 5212

2292 GUCCUAGA G CGUGUGGC 3927 GCCACACG GGCTAGCTACAACGA TCTAGGAC 5213

2294 CCUAGAGC G UGUGGCAC 3928 GTGCCACA GGCTAGCTACAACGA GCTCTAGG 5214

2296 UAGAGCGU G UGGCACCC 3929 GGGTGCCA GGCTAGCTACAACGA ACGCTCTA 5215

2299 AGCGUGUG G CACCCACG 3930 CGTGGGTG GGCTAGCTACAACGA CACACGCT 5216 2301 CGUGUGGC A CCCACGAU 3931 ATCGTGGG GGCTAGCTACAACGA GCCACACG 5217

2305 UGGCACCC A CGAUCACA 3932 TGTGATCG GGCTAGCTACAACGA GGGTGCCA 5218

2308 CACCCACG A UCACAGGA 3933 TCCTGTGA GGCTAGCTACAACGA CGTGGGTG 5219

2311 CCACGAUC A CAGGAAAC 3934 GTTTCCTG GGCTAGCTACAACGA GATCGTGG 5220

2318 CACAGGAA A CCUGGAGA 3935 TCTGCAGG GGCTAGCTACAACGA TTCCTGTG 5221

2327 CCUGGAGA A UCAGACGA 3936 TCGTCTGA GGCTAGCTACAACGA TCTCCAGG 5222

2332 AGAAUCAG A CGACAAGU 3937 ACTTGTCG GGCTAGCTACAACGA CTGATTCT 5223

2335 AUCAGACG A CAAGUAUU 3938 AATACTTG GGCTAGCTACAACGA CGTCTGAT 5224

2339 GACGACAA G UAUUGGGG 3939 CCCCAATA GGCTAGCTACAACGA TTGTCGTC 5225

2341 CGACAAGU A UUGGGGAA 3940 TTCCCCAA GGCTAGCTACAACGA ACTTGTCG 5226

2351 UGGGGAAA G CAUCGAAG 3941 CTTCGATG GGCTAGCTACAACGA TTTCCCCA 5227

2353 GGGAAAGC A UCGAAGUC 3942 GACTTCGA GGCTAGCTACAACGA GCTTTCCC 5228

2359 GCAUCGAA G UCUCAUGC 3943 GCATGAGA GGCTAGCTACAACGA TTCGATGC 5229

2364 GAAGUCUC A UGCACGGC 3944 GCCGTGCA GGCTAGCTACAACGA GAGACTTC 5230

2366 AGUCUCAU G CACGGCAU 3945 ATGCCGTG GGCTAGCTACAACGA ATGAGACT 5231

2368 UCUCAUGC A CGGCAUCU 3946 AGATGCCG GGCTAGCTACAACGA GCATGAGA 5232

2371 CAUGCACG G CAUCUGGG 3947 CCCAGATG GGCTAGCTACAACGA CGTGCATG 5233

2373 UGCACGGC A UCUGGGAA 3948 TTCCCAGA GGCTAGCTACAACGA GCCGTGCA 5234

2381 AUCUGGGA A UCCCCCUC 3949 GAGGGGGA GGCTAGCTACAACGA TCCCAGAT 5235

2391 CCCCCUCC A CAGAUCAU 3950 ATGATCTG GGCTAGCTACAACGA GGAGGGGG 5236

2395 CUCCACAG A UCAUGUGG 3951 CCACATGA GGCTAGCTACAACGA CTGTGGAG 5237

2398 CACAGAUC A UGUGGUUU 3952 AAACCACA GGCTAGCTACAACGA GATCTGTG 5238

2400 CAGAUCAU G UGGUUUAA 3953 TTAAACCA GGCTAGCTACAACGA ATGATCTG 5239

2403 AUCAUGUG G UUUAAAGA 3954 TCTTTAAA GGCTAGCTACAACGA CACATGAT 5240

2411 GUUUAAAG A UAAUGAGA 3955 TCTCATTA GGCTAGCTACAACGA CTTTAAAC 5241

2414 UAAAGAUA A UGAGACCC 3956 GGGTCTCA GGCTAGCTACAACGA TATCTTTA 5242

2419 AUAAUGAG A CCCUUGUA 3957 TACAAGGG GGCTAGCTACAACGA CTCATTAT 5243

2425 AGACCCUU G UAGAAGAC 3958 GTCTTCTA GGCTAGCTACAACGA AAGGGTCT 5244

2432 UGUAGAAG A CUCAGGCA 3959 TGCCTGAG GGCTAGCTACAACGA CTTCTACA 5245

2438 AGACUCAG G CAUUGUAU 3960 ATACAATG GGCTAGCTACAACGA CTGAGTCT 5246

2440 ACUCAGGC A UUGUAUUG 3961 CAATACAA GGCTAGCTACAACGA GCCTGAGT 5247

2443 CAGGCAUU G UAUUGAAG 3962 CTTCAATA GGCTAGCTACAACGA AATGCCTG 5248

2445 GGCAUUGU A UUGAAGGA 3963 TCCTTCAA GGCTAGCTACAACGA ACAATGCC 5249

2453 AUUGAAGG A UGGGAACC 3964 GGTTCCCA GGCTAGCTACAACGA CCTTCAAT 5250

2459 GGAUGGGA A CCGGAACC 3965 GGTTCCGG GGCTAGCTACAACGA TCCCATCC 5251

2465 GAACCGGA A CCUCACUA 3966 TAGTGAGG GGCTAGCTACAACGA TCCGGTTC 5252

2470 GGAACCUC A CUAUCCGC 3967 GCGGATAG GGCTAGCTACAACGA GAGGTTCC 5253

2473 ACCUCACU A UCCGCAGA 3968 TCTGCGGA GGCTAGCTACAACGA AGTGAGGT 5254

2477 CACUAUCC G CAGAGUGA 3969 TCACTCTG GGCTAGCTACAACGA GGATAGTG 5255

2482 UCCGCAGA G UGAGGAAG 3970 CTTCCTCA GGCTAGCTACAACGA TCTGCGGA 5256

2495 GAAGGAGG A CGAAGGCC 3971 GGCCTTCG GGCTAGCTACAACGA CCTCCTTC 5257

2501 GGACGAAG G CCUCUACA 3972 TGTAGAGG GGCTAGCTACAACGA CTTCGTCC 5258

2507 AGGCCUCU A CACCUGCC 3973 GGCAGGTG GGCTAGCTACAACGA AGAGGCCT 5259

2509 GCCUCUAC A CCUGCCAG 3974 CTGGCAGG GGCTAGCTACAACGA GTAGAGGC 5260

2513 CUACACCU G CCAGGCAU 3975 ATGCCTGG GGCTAGCTACAACGA AGGTGTAG 5261

2518 CCUGCCAG G CAUGCAGU 3976 ACTGCATG GGCTAGCTACAACGA CTGGCAGG 5262

2520 UGCCAGGC A UGCAGUGU 3977 ACACTGCA GGCTAGCTACAACGA GCCTGGCA 5263

2522 CCAGGCAU G CAGUGUUC 3978 GAACACTG GGCTAGCTACAACGA ATGCCTGG 5264

2525 GGCAUGCA G UGUUCUUG 3979 CAAGAACA GGCTAGCTACAACGA TGCATGCC 5265

2527 CAUGCAGU G UUCUUGGC 3980 GCCAAGAA GGCTAGCTACAACGA ACTGCATG 5266

2534 UGUUCUUG G CUGUGCAA 3981 TTGCACAG GGCTAGCTACAACGA CAAGAACA 5267

2537 UCUUGGCU G UGCAAAAG 3982 CTTTTGCA GGCTAGCTACAACGA AGCCAAGA 5268

2539 UUGGCUGU G CAAAAGUG 3983 CACTTTTG GGCTAGCTACAACGA ACAGCCAA 5269

2773 CUUAUGAU G CCAGCAAA 4037 TTTGCTGG GGCTAGCTACAACGA ATCATAAG 5323

2777 UGAUGCCA G CAAAUGGG 4038 CCCATTTG GGCTAGCTACAACGA TGGCATCA 5324

2781 GCCAGCAA A UGGGAAUU 4039 AATTCCCA GGCTAGCTACAACGA TTGCTGGC 5325

2787 AAAUGGGA A UUCCCCAG 4040 CTGGGGAA GGCTAGCTACAACGA TCCCATTT 5326

2798 CCCCAGAG A CCGGCUGA 4041 TCAGCCGG GGCTAGCTACAACGA CTCTGGGG 5327

2802 AGAGACCG G CUGAAGCU 4042 AGCTTCAG GGCTAGCTACAACGA CGGTCTCT 5328

2808 CGGCUGAA G CUAGGUAA 4043 TTACCTAG GGCTAGCTACAACGA TTCAGCCG 5329

2813 GAAGCUAG G UAAGCCUC 4044 GAGGCTTA GGCTAGCTACAACGA CTAGCTTC 5330

2817 CUAGGUAA G CCUCUUGG 4045 CCAAGAGG GGCTAGCTACAACGA TTACCTAG 5331

2825 GCCUCUUG G CCGUGGUG 4046 CACCACGG GGCTAGCTACAACGA CAAGAGGC 5332

2828 UCUUGGCC G UGGUGCCU 4047 AGGCACCA GGCTAGCTACAACGA GGCCAAGA 5333

2831 UGGCCGUG G UGCCUUUG 4048 CAAAGGCA GGCTAGCTACAACGA CACGGCCA 5334

2833 GCCGUGGU G CCUUUGGC 4049 GCCAAAGG GGCTAGCTACAACGA ACCACGGC 5335

2840 UGCCUUUG G CCAAGUGA 4050 TCACTTGG GGCTAGCTACAACGA CAAAGGCA 5336

2845 UUGGCCAA G UGAUUGAA 4051 TTCAATCA GGCTAGCTACAACGA TTGGCCAA 5337

2848 GCCAAGUG A UUGAAGCA 4052 TGCTTCAA GGCTAGCTACAACGA CACTTGGC 5338

2854 UGAUUGAA G CAGAUGCC 4053 GGCATCTG GGCTAGCTACAACGA TTCAATCA 5339

2858 UGAAGCAG A UGCCUUUG 4054 CAAAGGCA GGCTAGCTACAACGA CTGCTTCA 5340

2860 AAGCAGAU G CCUUUGGA 4055 TCCAAAGG GGCTAGCTACAACGA ATCTGCTT 5341

2869 CCUUUGGA A UUGACAAG 4056 CTTGTCAA GGCTAGCTACAACGA TCCAAAGG 5342

2873 UGGAAUUG A CAAGACAG 4057 CTGTCTTG GGCTAGCTACAACGA CAATTCCA 5343

2878 UUGACAAG A CAGCAACU 4058 AGTTGCTG GGCTAGCTACAACGA CTTGTCAA 5344

2881 ACAAGACA G CAACUUGC 4059 GCAAGTTG GGCTAGCTACAACGA TGTCTTGT 5345

2884 AGACAGCA A CUUGCAGG 4060 CCTGCAAG GGCTAGCTACAACGA TGCTGTCT 5346

2888 AGCAACUU G CAGGACAG 4061 CTGTCCTG GGCTAGCTACAACGA AAGTTGCT 5347

2893 CUUGCAGG A CAGUAGCA 4062 TGCTACTG GGCTAGCTACAACGA CCTGCAAG 5348

2896 GCAGGACA G UAGCAGUC 4063 GACTGCTA GGCTAGCTACAACGA TGTCCTGC 5349

2899 GGACAGUA G CAGUCAAA 4064 TTTGACTG GGCTAGCTACAACGA TACTGTCC 5350

2902 CAGUAGCA G UCAAAAUG 4065 CATTTTGA GGCTAGCTACAACGA TGCTACTG 5351

2908 CAGUCAAA A UGUUGAAA 4066 TTTCAACA GGCTAGCTACAACGA TTTGACTG 5352

2910 GUCAAAAU G UUGAAAGA 4067 TCTTTCAA GGCTAGCTACAACGA ATTTTGAC 5353

2923 AAGAAGGA G CAACACAC 4068 GTGTGTTG GGCTAGCTACAACGA TCCTTCTT 5354

2926 AAGGAGCA A CACACAGU 4069 ACTGTGTG GGCTAGCTACAACGA TGCTCCTT 5355

2928 GGAGCAAC A CACAGUGA 4070 TCACTGTG GGCTAGCTACAACGA GTTGCTCC 5356

2930 AGCAACAC A CAGUGAGC 4071 GCTCACTG GGCTAGCTACAACGA GTGTTGCT 5357

2933 AACACACA G UGAGCAUC 4072 GATGCTCA GGCTAGCTACAACGA TGTGTGTT 5358

2937 CACAGUGA G CAUCGAGC 4073 GCTCGATG GGCTAGCTACAACGA TCACTGTG 5359

2939 CAGUGAGC A UCGAGCUC 4074 GAGCTCGA GGCTAGCTACAACGA GCTCACTG 5360

2944 AGCAUCGA G CUCUGAUG 4075 CATGAGAG GGCTAGCTACAACGA TCGATGCT 5361

2950 GAGCUCUC A UGUCUGAA 4076 TTCAGACA GGCTAGCTACAACGA GAGAGCTC 5362

2952 GCUCUCAU G UCUGAACU 4077 AGTTCAGA GGCTAGCTACAACGA ATGAGAGC 5363

2958 AUGUCUGA A CUCAAGAU 4078 ATCTTGAG GGCTAGCTACAACGA TCAGACAT 5364

2965 AACUCAAG A UCCUCAUU 4079 AATGAGGA GGCTAGCTACAACGA CTTGAGTT 5365

2971 AGAUCCUC A UUCAUAUU 4080 AATATGAA GGCTAGCTACAACGA GAGGATCT 5366

2975 CCUCAUUC A UAUUGGUC 4081 GACCAATA GGCTAGCTACAACGA GAATGAGG 5367

2977 UCAUUCAU A UUGGUCAC 4082 GTGACCAA GGCTAGCTACAACGA ATGAATGA 5368

2981 UCAUAUUG G UCACCAUC 4083 GATGGTGA GGCTAGCTACAACGA CAATATGA 5369

2984 UAUUGGUC A CCAUCUCA 4084 TGAGATGG GGCTAGCTACAACGA GACCAATA 5370

2987 UGGUCACC A UCUCAAUG 4085 CATTGAGA GGCTAGCTACAACGA GGTGACCA 5371

2993 CCAUCUCA A UGUGGUCA 4086 TGACCACA GGCTAGCTACAACGA TGAGATGG 5372

2995 AUCUCAAU G UGGUCAAC 4087 GTTGACCA GGCTAGCTACAACGA ATTGAGAT 5373

2998 UCAAUGUG G UCAACCUU 4088 AAGGTTGA GGCTAGCTACAACGA CACATTGA 5374

3002 UGUGGUCA A CCUUCUAG 4089 CTAGAAGG GGCTAGCTACAACGA TGACCACA 5375 3011 CCUUCUAG G UGCCUGUA 4090 TACAGGCA GGCTAGCTACAACGA CTAGAAGG 5376

3013 UUCUAGGU G CCUGUACC 4091 GGTACAGG GGCTAGCTACAACGA ACCTAGAA 5377

3017 AGGUGCCU G UACCAAGC 4092 GCTTGGTA GGCTAGCTACAACGA AGGCACCT 5378

3019 GUGCCUGU A CCAAGCCA 4093 TGGCTTGG GGCTAGCTACAACGA ACAGGCAC 5379

3024 UGUACCAA G CCAGGAGG 4094 CCTCCTGG GGCTAGCTACAACGA TTGGTACA 5380

3033 CCAGGAGG G CCACUCAU 4095 ATGAGTGG GGCTAGCTACAACGA CCTCCTGG 5381

3036 GGAGGGCC A CUCAUGGU 4096 ACCATGAG GGCTAGCTACAACGA GGCCCTCC 5382

3040 GGCCACUC A UGGUGAUU 4097 AATCACCA GGCTAGCTACAACGA GAGTGGCC 5383

3043 CACUCAUG G UGAUUGUG 4098 CACAATCA GGCTAGCTACAACGA CATGAGTG 5384

3046 UCAUGGUG A UUGUGGAA 4099 TTCCACAA GGCTAGCTACAACGA CACCATGA 5385

3049 UGGUGAUU G UGGAAUUC 4100 GAATTCCA GGCTAGCTACAACGA AATCACCA 5386

3054 AUUGUGGA A UUCUGCAA 4101 TTGCAGAA GGCTAGCTACAACGA TCCACAAT 5387

3059 GGAAUUCU G CAAAUUUG 4102 CAAATTTG GGCTAGCTACAACGA AGAATTCC 5388

3063 UUCUGCAA A UUUGGAAA 4103 TTTCCAAA GGCTAGCTACAACGA TTGCAGAA 5389

3071 AUUUGGAA A CCUGUGCA 4104 TGGACAGG GGCTAGCTACAACGA TTCCAAAT 5390

3075 GGAAACCU G UCCACUUA 4105 TAAGTGGA GGCTAGCTACAACGA AGGTTTCC 5391

3079 ACCUGUCC A CUUACCUG 4106 CAGGTAAG GGCTAGCTACAACGA GGACAGGT 5392

3083 GUCCACUU A CCUGAGGA 4107 TCCTCAGG GGCTAGCTACAACGA AAGTGGAC 5393

3092 CCUGAGGA G CAAGAGAA 4108 TTCTCTTG GGCTAGCTACAACGA TCCTCAGG 5394

3101 CAAGAGAA A UGAAUUUG 4109 CAAATTCA GGCTAGCTACAACGA TTCTCTTG 5395

3105 AGAAAUGA A UUUGUCCC 4110 GGGACAAA GGCTAGCTACAACGA TCATTTCT 5396

3109 AUGAAUUU G UCCCCUAC 4111 GTAGGGGA GGCTAGCTACAACGA AAATTCAT 5397

3116 UGUCCCCU A CAAGACCA 4112 TGGTCTTG GGCTAGCTACAACGA AGGGGACA 5398

3121 CCUACAAG A CCAAAGGG 4113 CCCTTTGG GGCTAGCTACAACGA CTTGTAGG 5399

3130 CCAAAGGG G CACGAUUC 4114 GAATCGTG GGCTAGCTACAACGA CCCTTTGG 5400

3132 AAAGGGGC A CGAUUCCG 4115 CGGAATCG GGCTAGCTACAACGA GCCCCTTT 5401

3135 GGGGCACG A UUCCGUCA 4116 TGACGGAA GGCTAGCTACAACGA CGTGCCCC 5402

3140 ACGAUUCC G UCAAGGGA 4117 TCCCTTGA GGCTAGCTACAACGA GGAATCGT 5403

3152 AGGGAAAG A CUACGUUG 4118 CAACGTAG GGCTAGCTACAACGA CTTTCCCT 5404

3155 GAAAGACU A CGUUGGAG 4119 CTCCAACG GGCTAGCTACAACGA AGTCTTTC 5405

3157 AAGACUAC G UUGGAGCA 4120 TGCTCCAA GGCTAGCTACAACGA GTAGTCTT 5406

3163 ACGUUGGA G CAAUCCCU 4121 AGGGATTG GGCTAGCTACAACGA TCCAACGT 5407

3166 UUGGAGCA A UCCCUGUG 4122 CACAGGGA GGCTAGCTACAACGA TGCTCCAA 5408

3172 CAAUCCCU G UGGAUCUG 4123 CAGATCCA GGCTAGCTACAACGA AGGGATTG 5409

3176 CCCUGUGG A UCUGAAAC 4124 GTTTCAGA GGCTAGCTACAACGA CCACAGGG 5410

3183 GAUCUGAA A CGGCGCUU 4125 AAGCGCCG GGCTAGCTACAACGA TTCAGATC 5411

3186 CUGAAACG G CGCUUGGA 4126 TCCAAGCG GGCTAGCTACAACGA GGTTTCAG 5412

3188 GAAACGGC G CUUGGACA 4127 TGTCCAAG GGCTAGCTACAACGA GCCGTTTC 5413

3194 GCGCUUGG A CAGCAUCA 4128 TGATGCTG GGCTAGCTACAACGA CCAAGCGC 5414

3197 CUUGGACA G CAUCACCA 4129 TGGTGATG GGCTAGCTACAACGA TGTCCAAG 5415

3199 UGGACAGC A UCACCAGU 4130 ACTGGTGA GGCTAGCTACAACGA GCTGTCCA 5416

3202 ACAGCAUC A CCAGUAGC 4131 GCTACTGG GGCTAGCTACAACGA GATGCTGT 5417

3206 CAUCACCA G UAGCCAGA 4132 TCTGGCTA GGCTAGCTACAACGA TGGTGATG 5418

3209 CACCAGUA G CCAGAGCU 4133 AGCTCTGG GGCTAGCTACAACGA TACTGGTG 5419

3215 UAGCCAGA G CUCAGCCA 4134 TGGCTGAG GGCTAGCTACAACGA TCTGGCTA 5420

3220 AGAGCUCA G CCAGCUCU 4135 AGAGCTGG GGCTAGCTACAACGA TGAGCTCT 5421

3224 CUCAGCCA G CUCUGGAU 4136 ATCCAGAG GGCTAGCTACAACGA TGGCTGAG 5422

3231 AGCUCUGG A UUUGUGGA 4137 TCCAGAAA GGCTAGCTACAACGA CCAGAGCT 5423

3235 CUGGAUUU G UGGAGGAG 4138 CTCCTCCA GGCTAGCTACAACGA AAATCCAG 5424

3246 GAGGAGAA G UCCCUCAG 4139 CTGAGGGA GGCTAGCTACAACGA TTCTCCTC 5425

3254 GUCCCUCA G UGAUGUAG 4140 CTACATCA GGCTAGCTACAACGA TGAGGGAC 5426

3257 CCUCAGUG A UGUAGAAG 4141 CTTCTACA GGCTAGCTACAACGA CACTGAGG 5427

3259 UCAGUGAU G UAGAAGAA 4142 TTCTTCTA GGCTAGCTACAACGA ATCACTGA 5428 3274 AAGAGGAA G CUCCUGAA 4143 TTCAGGAG GGCTAGCTACAACGA TTCCTCTT 5429

3284 UCCUGAAG A UCUGUAUA 4144 TATACAGA GGCTAGCTACAACGA CTTCAGGA 5430

3288 GAAGAUCU G UAUAAGGA 4145 TCCTTATA GGCTAGCTACAACGA AGATCTTC 5431

3290 AGAUCUGU A UAAGGACU 4146 AGTCCTTA GGCTAGCTACAACGA ACAGATCT 5432

3296 GUAUAAGG A CUUCCUGA 4147 TCAGGAAG GGCTAGCTACAACGA CCTTATAC 5433

3304 ACUUCCUG A CCUUGGAG 4148 CTCCAAGG GGCTAGCTACAACGA CAGGAAGT 5434

3312 ACCUUGGA G CAUCUCAU 4149 ATGAGATG GGCTAGCTACAACGA TCCAAGGT 5435

3314 CUUGGAGC A UCUCAUCU 4150 AGATGAGA GGCTAGCTACAACGA GCTCCAAG 5436

3319 AGCAUCUC A UCUGUUAC 4151 GTAACAGA GGCTAGCTACAACGA GAGATGCT 5437

3323 UCUCAUCU G UUACAGCU 4152 AGCTGTAA GGCTAGCTACAACGA AGATGAGA 5438

3326 CAUCUGUU A CAGCUUCC 4153 GGAAGCTG GGCTAGCTACAACGA AACAGATG 5439

3329 CUGUUACA G CUUCCAAG 4154 CTTGGAAG GGCTAGCTACAACGA TGTAACAG 5440

3337 GCUUCCAA G UGGCUAAG 4155 CTTAGCGA GGCTAGCTACAACGA TTGGAAGC 5441

3340 UCCAAGUG G CUAAGGGC 4156 GCCCTTAG GGCTAGCTACAACGA CACTTGGA 5442

3347 GGCUAAGG G CAUGGAGU 4157 ACTCCATG GGCTAGCTACAACGA CCTTAGCC 5443

3349 CUAAGGGC A UGGAGUUC 4158 GAACTCCA GGCTAGCTACAACGA GCCCTTAG 5444

3354 GGCAUGGA G UUCUUGGC 4159 GCCAAGAA GGCTAGCTACAACGA TCCATGCC 5445

3361 AGUUCUUG G CAUCGCGA 4160 TCGCGATG GGCTAGCTACAACGA CAAGAACT 5446

3363 UUCUUGGC A UCGCGAAA 4161 TTTCGCGA GGCTAGCTACAACGA GCCAAGAA 5447

3366 UUGGCAUC G CGAAAGUG 4162 CACTTTCG GGCTAGCTACAACGA GATGCCAA 5448

3372 UCGCGAAA G UGUAUCCA 4163 TGGATACA GGCTAGCTACAACGA TTTCGCGA 5449

3374 GCGAAAGU G UAUCCACA 4164 TGTGGATA GGCTAGCTACAACGA ACTTTCGC 5450

3376 GAAAGUGU A UCCACAGG 4165 CCTGTGGA GGCTAGCTACAACGA ACACTTTC 5451

3380 GUGUAUCC A CAGGGACC 4166 GGTCCCTG GGCTAGCTACAACGA GGATACAC 5452

3386 CCACAGGG A CCUGGCGG 4167 CCGCCAGG GGCTAGCTACAACGA CCCTGTGG 5453

3391 GGGACCUG G CGGCACGA 4168 TCGTGCCG GGCTAGCTACAACGA CAGGTCCC 5454

3394 ACCUGGCG G CACGAAAU 4169 ATTTCGTG GGCTAGCTACAACGA CGCCAGGT 5455

3396 CUGGCGGC A CGAAAUAU 4170 ATATTTCG GGCTAGCTACAACGA GCCGCCAG 5456

3401 GGCACGAA A UAUCCUCU 4171 AGAGGATA GGCTAGCTACAACGA TTCGTGCC 5457

3403 CACGAAAU A UCCUCUUA 4172 TAAGAGGA GGCTAGCTACAACGA ATTTCGTG 5458

3411 AUCCUCUU A UCGGAGAA 4173 TTCTCCGA GGCTAGCTACAACGA AAGAGGAT 5459

3422 GGAGAAGA A CGUGGUUA 4174 TAACCACG GGCTAGCTACAACGA TCTTCTCC 5460

3424 AGAAGAAC G UGGUUAAA 4175 TTTAACCA GGCTAGCTACAACGA GTTCTTCT 5461

3427 AGAACGUG G UUAAAAUC 4176 GATTTTAA GGCTAGCTACAACGA CACGTTCT 5462

3433 UGGUUAAA A UCUGUGAC 4177 GTCACAGA GGCTAGCTACAACGA TTTAACCA 5463

3437 UAAAAUCU G UGACUUUG 4178 CAAAGTCA GGCTAGCTACAACGA AGATTTTA 5464

3440 AAUCUGUG A CUUUGGCU 4179 AGCCAAAG GGCTAGCTACAACGA CACAGATT 5465

3446 UGACUUUG G CUUGGCCC 4180 GGGCCAAG GGCTAGCTACAACGA CAAAGTCA 5466

3451 UUGGCUUG G CCCGGGAU 4181 ATCCCGGG GGCTAGCTACAACGA CAAGCCAA 5467

3458 GGCCCGGG A UAUUUAUA 4182 TATAAATA GGCTAGCTACAACGA CCCGGGCC 5468

3460 CCCGGGAU A UUUAUAAA 4183 TTTATAAA GGCTAGCTACAACGA ATCCCGGG 5469

3464 GGAUAUUU A UAAAGAUC 4184 GATCTTTA GGCTAGCTACAACGA AAATATCC 5470

3470 UUAUAAAG A UCCAGAUU 4185 AATCTGGA GGCTAGCTACAACGA CTTTATAA 5471

3476 AGAUCCAG A UUAUGUCA 4186 TGACATAA GGCTAGCTACAACGA CTGGATCT 5472

3479 UCCAGAUU A UGUCAGAA 4187 TTCTGACA GGCTAGCTACAACGA AATCTGGA 5473

3481 CAGAUUAU G UCAGAAAA 4188 TTTTCTGA GGCTAGCTACAACGA ATAATCTG 5474

3494 AAAAGGAG A UGCUCGCC 4189 GGCGAGCA GGCTAGCTACAACGA CTCCTTTT 5475

3496 AAGGAGAU G CUCGCCUC 4190 GAGGCGAG GGCTAGCTACAACGA ATCTCCTT 5476

3500 AGAUGCUC G CCUCCCUU 4191 AAGGGAGG GGCTAGCTACAACGA GAGCATCT 5477

3513 CCUUUGAA A UGGAUGGC 4192 GCCATCCA GGCTAGCTACAACGA TTCAAAGG 5478

3517 UGAAAUGG A UGGCCCCA 4193 TGGGGCCA GGCTAGCTACAACGA CCATTTCA 5479

3520 AAUGGAUG G CCCCAGAA 4194 TTCTGGGG GGCTAGCTACAACGA CATCCATT 5480

3529 CCCCAGAA A CAAUUUUU 4195 AAAAATTG GGCTAGCTACAACGA TTCTGGGG 5481 3532 CAGAAACA A UUUUUGAC 4196 GTCAAAAA GGCTAGCTACAACGA TGTTTCTG 5482

3539 AAUUUUUG A CAGAGUGU 4197 ACACTCTG GGCTAGCTACAACGA CAAAAATT 5483

3544 UUGACAGA G UGUACACA 4198 TGTGTACA GGCTAGCTACAACGA TCTGTCAA 5484

3546 GACAGAGU G UACACAAU 4199 ATTGTGTA GGCTAGCTACAACGA ACTCTGTC 5485

3548 CAGAGUGU A CACAAUCC 4200 GGATTGTG GGCTAGCTACAACGA ACACTCTG 5486

3550 GAGUGUAC A CAAUCCAG 4201 CTGGATTG GGCTAGCTACAACGA GTACACTC 5487

3553 UGUACACA A UCCAGAGU 4202 ACTCTGGA GGCTAGCTACAACGA TGTGTACA 5488

3560 AAUCCAGA G UGACGUCU 4203 AGACGTCA GGCTAGCTACAACGA TCTGGATT 5489

3563 CCAGAGUG A CGUCUGGU 4204 ACCAGACG GGCTAGCTACAACGA CACTCTGG 5490

3565 AGAGUGAC G UCUGGUCU 4205 AGACCAGA GGCTAGCTACAACGA GTCACTCT 5491

3570 GACGUCUG G UCUUUUGG 4206 CCAAAAGA GGCTAGCTACAACGA CAGACGTC 5492

3578 GUCUUUUG G UGUUUUGC 4207 GCAAAACA GGCTAGCTACAACGA CAAAAGAC 5493

3580 CUUUUGGU G UUUUGCUG 4208 CAGCAAAA GGCTAGCTACAACGA ACCAAAAG 5494

3585 GGUGUUUU G CUGUGGGA 4209 TCCCACAG GGCTAGCTACAACGA AAAACACC 5495

3588 GUUUUGCU G UGGGAAAU 4210 ATTTCCCA GGCTAGCTACAACGA AGCAAAAC 5496

3595 UGUGGGAA A UAUUUUCC 4211 GGAAAATA GGCTAGCTACAACGA TTCCCACA 5497

3597 UGGGAAAU A UUUUCCUU 4212 AAGGAAAA GGCTAGCTACAACGA ATTTCCCA 5498

3608 UUCCUUAG G UGCUUCUC 4213 GAGAAGCA GGCTAGCTACAACGA CTAAGGAA 5499

3610 CCUUAGGU G CUUCUCCA 4214 TGGAGAAG GGCTAGCTACAACGA ACCTAAGG 5500

3618 GCUUCUCC A UAUCCUGG 4215 CCAGGATA GGCTAGCTACAACGA GGAGAAGC 5501

3620 UUCUCCAU A UCCUGGGG 4216 CCCCAGGA GGCTAGCTACAACGA ATGGAGAA 5502

3628 AUCCUGGG G UAAAGAUU 4217 AATCTTTA GGCTAGCTACAACGA CCCAGGAT 5503

3634 GGGUAAAG A UUGAUGAA 4218 TTCATCAA GGCTAGCTACAACGA CTTTACCC 5504

3638 AAAGAUUG A UGAAGAAU 4219 ATTCTTCA GGCTAGCTACAACGA CAATCTTT 5505

3645 GAUGAAGA A UUUUGUAG 4220 CTACAAAA GGCTAGCTACAACGA TCTTCATC 5506

3650 AGAAUUUU G UAGGCGAU 4221 ATCGCCTA GGCTAGCTACAACGA AAAATTCT 5507

3654 UUUUGUAG G CGAUUGAA 4222 TTCAATCG GGCTAGCTACAACGA CTACAAAA 5508

3657 UGUAGGCG A UUGAAAGA 4223 TCTTTCAA GGCTAGCTACAACGA CGCCTACA 5509

3670 AAGAAGGA A CUAGAAUG 4224 CATTCTAG GGCTAGCTACAACGA TCCTTCTT 5510

3676 GAACUAGA A UGAGGGCC 4225 GGCCCTCA GGCTAGCTACAACGA TCTAGTTC 5511

3682 GAAUGAGG G CCCCUGAU 4226 ATCAGGGG GGCTAGCTACAACGA CCTCATTC 5512

3689 GGCCCCUG A UUAUACUA 4227 TAGTATAA GGCTAGCTACAACGA CAGGGGCC 5513

3692 CCCUGAUU A UACUACAC 4228 GTGTAGTA GGCTAGCTACAACGA AATCAGGG 5514

3694 CUGAUUAU A CUACACCA 4229 TGGTGTAG GGCTAGCTACAACGA ATAATCAG 5515

3697 AUUAUACU A CACCAGAA 4230 TTCTGGTG GGCTAGCTACAACGA AGTATAAT 5516

3699 UAUACUAC A CCAGAAAU 4231 ATTTCTGG GGCTAGCTACAACGA GTAGTATA 5517

3706 CACCAGAA A UGUACCAG 4232 CTGGTACA GGCTAGCTACAACGA TTCTGGTG 5518

3708 CCAGAAAU G UACCAGAC 4233 GTCTGGTA GGCTAGCTACAACGA ATTTCTGG 5519

3710 AGAAAUGU A CCAGACCA 4234 TGGTCTGG GGCTAGCTACAACGA ACATTTCT 5520

3715 UGUACCAG A CCAUGCUG 4235 CAGCATGG GGCTAGCTACAACGA CTGGTACA 5521

3718 ACCAGACC A UGCUGGAC 4236 GTCCAGCA GGCTAGCTACAACGA GGTCTGGT 5522

3720 CAGACCAU G CUGGACUG 4237 CAGTCCAG GGCTAGCTACAACGA ATGGTCTG 5523

3725 CAUGCUGG A CUGCUGGC 4238 GCCAGCAG GGCTAGCTACAACGA CCAGCATG 5524

3728 GCUGGACU G CUGGCACG 4239 CGTGCCAG GGCTAGCTACAACGA AGTCCAGC 5525

3732 GACUGCUG G CACGGGGA 4240 TCCCCGTG GGCTAGCTACAACGA CAGCAGTC 5526

3734 CUGCUGGC A CGGGGAGC 4241 GCTCCCCG GGCTAGCTACAACGA GCCAGCAG 5527

3741 CACGGGGA G CCCAGUCA 4242 TGACTGGG GGCTAGCTACAACGA TCCCCGTG 5528

3746 GGAGCCCA G UCAGAGAC 4243 GTCTCTGA GGCTAGCTACAACGA TGGGCTCC 5529

3753 AGUCAGAG A CCCACGUU 4244 AACGTGGG GGCTAGCTACAACGA CTCTGACT 5530

3757 AGAGACCC A CGUUUUCA 4245 TGAAAACG GGCTAGCTACAACGA GGGTCTCT 5531

3759 AGACCCAC G UUUUCAGA 4246 TCTGAAAA GGCTAGCTACAACGA GTGGGTCT 5532

3768 UUUUCAGA G UUGGUGGA 4247 TCCACCAA GGCTAGCTACAACGA TCTGAAAA 5533

3772 CAGAGUUG G UGGAACAU 4248 ATGTTCCA GGCTAGCTACAACGA CAACTCTG 5534 3777 UUGGUGGA A CAUUUGGG 4249 CCCAAATG GGCTAGCTACAACGA TCCACCAA 5535

3779 GGUGGAAC A UUUGGGAA 4250 TTCCCAAA GGCTAGCTACAACGA GTTCCACC 5536

3788 UUUGGGAA A UCUCUUGC 4251 GCAAGAGA GGCTAGCTACAACGA TTCCCAAA 5537

3795 AAUCUCUU G CAAGCUAA 4252 TTAGCTTG GGCTAGCTACAACGA AAGAGATT 5538

3799 UCUUGCAA G CUAAUGCU 4253 AGCATTAG GGCTAGCTACAACGA TTGCAAGA 5539

3803 GCAAGCUA A UGCUCAGC 4254 GCTGAGCA GGCTAGCTACAACGA TAGCTTGC 5540

3805 AAGCUAAU G CUCAGCAG 4255 CTGCTGAG GGCTAGCTACAACGA ATTAGCTT 5541

3810 AAUGCUCA G CAGGAUGG 4256 CCATCCTG GGCTAGCTACAACGA TGAGCATT 5542

3815 UCAGCAGG A UGGCAAAG 4257 CTTTGCCA GGCTAGCTACAACGA CCTGCTGA 5543

3818 GCAGGAUG G CAAAGACU 4258 AGTCTTTG GGCTAGCTACAACGA CATCCTGC 5544

3824 UGGCAAAG A CUACAUUG 4259 CAATGTAG GGCTAGCTACAACGA CTTTGCCA 5545

3827 CAAAGACU A CAUUGUUC 4260 GAACAATG GGCTAGCTACAACGA AGTCTTTG 5546

3829 AAGACUAC A UUGUUCUU 4261 AAGAACAA GGCTAGCTACAACGA GTAGTCTT 5547

3832 ACUACAUU G UUCUUCCG 4262 CGGAAGAA GGCTAGCTACAACGA AATGTAGT 5548

3841 UUCUUCCG A UAUCAGAG 4263 CTCTGATA GGCTAGCTACAACGA CGGAAGAA 5549

3843 CUUCCGAU A UCAGAGAC 4264 GTCTCTGA GGCTAGCTACAACGA ATCGGAAG 5550

3850 UAUCAGAG A CUUUGAGC 4265 GCTCAAAG GGCTAGCTACAACGA CTCTGATA 5551

3857 GACUUUGA G CAUGGAAG 4266 CTTCCATG GGCTAGCTACAACGA TCAAAGTC 5552

3859 CUUUGAGC A UGGAAGAG 4267 CTCTTCCA GGCTAGCTACAACGA GCTCAAAG 5553

3869 GGAAGAGG A UUCUGGAC 4268 GTCCAGAA GGCTAGCTACAACGA CCTCTTCC 5554

3876 GAUUCUGG A CUCUCUGU 4269 AGAGAGAG GGCTAGCTACAACGA CCAGAATC 5555

3885 CUCUCUGU G CCUACCUC 4270 GAGGTAGG GGCTAGCTACAACGA AGAGAGAG 5556

3889 CUCUGCCU A CCUCACCU 4271 AGGTGAGG GGCTAGCTACAACGA AGGCAGAG 5557

3894 CCUACCUC A CCUGUUUC 4272 GAAACAGG GGCTAGCTACAACGA GAGGTAGG 5558

3898 CCUCACCU G UUUCCUGU 4273 AGAGGAAA GGCTAGCTACAACGA AGGTGAGG 5559

3905 UGUUUCCU G UAUGGAGG 4274 CCTCCATA GGCTAGCTACAACGA AGGAAACA 5560

3907 UUUCCUGU A UGGAGGAG 4275 CTCCTCCA GGCTAGCTACAACGA ACAGGAAA 5561

3922 AGGAGGAA G UAUGUGAC 4276 GTCACATA GGCTAGCTACAACGA TTCCTCCT 5562

3924 GAGGAAGU A UGUGACCC 4277 GGGTCACA GGCTAGCTACAACGA ACTTCCTC 5563

3926 GGAAGUAU G UGACCCCA 4278 TGGGGTCA GGCTAGCTACAACGA ATACTTCC 5564

3929 AGUAUGUG A CCCCAAAU 4279 ATTTGGGG GGCTAGCTACAACGA CACATACT 5565

3936 GACCCCAA A UUCCAUUA 4280 TAATGGAA GGCTAGCTACAACGA TTGGGGTC 5566

3941 CAAAUUCC A UUAUGACA 4281 TGTCATAA GGCTAGCTACAACGA GGAATTTG 5567

3944 AUUCCAUU A UGACAACA 4282 TGTTGTCA GGCTAGCTACAACGA AATGGAAT 5568

3947 CCAUUAUG A CAACAGAG 4283 CTGTGTTG GGCTAGCTACAACGA CATAATGG 5569

3950 UUAUGACA A CACAGCAG 4284 CTGCTGTG GGCTAGCTACAACGA TGTCATAA 5570

3952 AUGACAAC A CAGCAGGA 4285 TCCTGCTG GGCTAGCTACAACGA GTTGTCAT 5571

3955 ACAACACA G CAGGAAUC 4286 GATTCCTG GGCTAGCTACAACGA TGTGTTGT 5572

3961 CAGCAGGA A UCAGUCAG 4287 CTGACTGA GGCTAGCTACAACGA TCCTGCTG 5573

3965 AGGAAUCA G UCAGUAUC 4288 GATACTGA GGCTAGCTACAACGA TGATTCCT 5574

3969 AUCAGUCA G UAUCUGCA 4289 TGCAGATA GGCTAGCTACAACGA TGACTGAT 5575

3971 CAGUCAGU A UCUGCAGA 4290 TCTGCAGA GGCTAGCTACAACGA ACTGACTG 5576

3975 CAGUAUCU G CAGAACAG 4291 CTGTTCTG GGCTAGCTACAACGA AGATACTG 5577

3980 UCUGCAGA A CAGUAAGC 4292 GCTTACTG GGCTAGCTACAACGA TCTGCAGA 5578

3983 GCAGAACA G UAAGCGAA 4293 TTCGCTTA GGCTAGCTACAACGA TGTTCTGC 5579

3987 AACAGUAA G CGAAAGAG 4294 CTCTTTCG GGCTAGCTACAACGA TTACTGTT 5580

3995 GCGAAAGA G CCGGCCUG 4295 CAGGCCGG GGCTAGCTACAACGA TCTTTCGC 5581

3999 AAGAGCCG G CCUGUGAG 4296 CTCACAGG GGCTAGCTACAACGA CGGCTCTT 5582

4003 GCCGGCCU G UGAGUGUA 4297 TACACTCA GGCTAGCTACAACGA AGGCCGGC 5583

4007 GCCUGUGA G UGUAAAAA 4298 TTTTTACA GGCTAGCTACAACGA TCACAGGC 5584

4009 CUGUGAGU G UAAAAACA 4299 TGTTTTTA GGCTAGCTACAACGA ACTCACAG 5585

4015 GUGUAAAA A CAUUUGAA 4300 TTCAAATG GGCTAGCTACAACGA TTTTACAC 5586

4017 GUAAAAAC A UUUGAAGA 4301 TCTTCAAA GGCTAGCTACAACGA GTTTTTAC 5587 4025 AUUUGAAG A UAUCCCGU 4302 ACGGGATA GGCTAGCTACAACGA CTTCAAAT 5588

4027 UUGAAGAU A UCCCGUUA 4303 TAACGGGA GGCTAGCTACAACGA ATCTTCAA 5589

4032 GAUAUCCC G UUAGAAGA 4304 TCTTCTAA GGCTAGCTACAACGA GGGATATC 5590

4041 UUAGAAGA A CCAGAAGU 4305 ACTTCTGG GGCTAGCTACAACGA TCTTCTAA 5591

4048 AACCAGAA G UAAAAGUA 4306 TACTTTTA GGCTAGCTACAACGA TTCTGGTT 5592

4054 AAGUAAAA G UAAUCCCA 4307 TGGGATTA GGCTAGCTACAACGA TTTTACTT 5593

4057 UAAAAGUA A UCCCAGAU 4308 ATCTGGGA GGCTAGCTACAACGA TACTTTTA 5594

4064 AAUCCCAG A UGACAACC 4309 GGTTGTCA GGCTAGCTACAACGA CTGGGATT 5595

4067 CCCAGAUG A CAACCAGA 4310 TCTGGTTG GGCTAGCTACAACGA CATCTGGG 5596

4070 AGAUGACA A CCAGACGG 4311 CCGTCTGG GGCTAGCTACAACGA TGTCATCT 5597

4075 ACAACCAG A CGGACAGU 4312 ACTGTCCG GGCTAGCTACAACGA CTGGTTGT 5598

4079 CCAGACGG A CAGUGGUA 4313 TACCACTG GGCTAGCTACAACGA CCGTCTGG 5599

4082 GACGGACA G UGGUAUGG 4314 CCATACCA GGCTAGCTACAACGA TGTCCGTC 5600

4085 GGACAGUG G UAUGGUUC 4315 GAACCATA GGCTAGCTACAACGA CACTGTCC 5601

4087 ACAGUGGU A UGGUUCUU 4316 AAGAACCA GGCTAGCTACAACGA ACCACTGT 5602

4090 GUGGUAUG G UUCUUGGC 4317 GGCAAGAA GGCTAGCTACAACGA CATACCAC 5603

4096 UGGUUCUU G CCUCAGAA 4318 TTCTGAGG GGCTAGCTACAACGA AAGAACCA 5604

4107 UCAGAAGA G CUGAAAAC 4319 GTTTTCAG GGCTAGCTACAACGA TCTTCTGA 5605

4114 AGCUGAAA A CUUUGGAA 4320 TTCCAAAG GGCTAGCTACAACGA TTTCAGCT 5606

4124 UUUGGAAG A CAGAACCA 4321 TGGTTCTG GGCTAGCTACAACGA CTTCCAAA 5607

4129 AAGACAGA A CCAAAUUA 4322 TAATTTGG GGCTAGCTACAACGA TCTGTCTT 5608

4134 AGAACCAA A UUAUCUCC 4323 GGAGATAA GGCTAGCTACAACGA TTGGTTCT 5609

4137 ACCAAAUU A UCUCCAUC 4324 GATGGAGA GGCTAGCTACAACGA AATTTGGT 5610

4143 UUAUCUCC A UCUUUUGG 4325 CCAAAAGA GGCTAGCTACAACGA GGAGATAA 5611

4151 AUCUUUUG G UGGAAUGG 4326 CCATTCCA GGCTAGCTACAACGA CAAAAGAT 5612

4156 UUGGUGGA A UGGUGCCC 4327 GGGCACCA GGCTAGCTACAACGA TCCACCAA 5613

4159 GUGGAAUG G UGCCCAGC 4328 GCTGGGCA GGCTAGCTACAACGA CATTCCAC 5614

4161 GGAAUGGU G CCCAGCAA 4329 TTGCTGGG GGCTAGCTACAACGA ACCATTCC 5615

4166 GGUGCCCA G CAAAAGCA 4330 TGCTTTTG GGCTAGCTACAACGA TGGGCACC 5616

4172 CAGCAAAA G CAGGGAGU 4331 ACTCCCTG GGCTAGCTACAACGA TTTTGCTG 5617

4179 AGCAGGGA G UCUGUGGC 4332 GCCACAGA GGCTAGCTACAACGA TCCCTGCT 5618

4183 GGGAGUCU G UGGCAUCU 4333 AGATGCCA GGCTAGCTACAACGA AGACTCCC 5619

4186 AGUCUGUG G CAUCUGAA 4334 TTCAGATG GGCTAGCTACAACGA CACAGACT 5620

4188 UCUGUGGC A UCUGAAGG 4335 CCTTCAGA GGCTAGCTACAACGA GCCACAGA 5621

4196 AUCUGAAG G CUCAAACC 4336 GGTTTGAG GGCTAGCTACAACGA CTTCAGAT 5622

4202 AGGCUCAA A CCAGACAA 4337 TTGTCTGG GGCTAGCTACAACGA TTGAGCCT 5623

4207 CAAACCAG A CAAGCGGC 4338 GCCGCTTG GGCTAGCTACAACGA CTGGTTTG 5624

4211 CCAGACAA G CGGCUACC 4339 GGTAGCCG GGCTAGCTACAACGA TTGTCTGG 5625

4214 GACAAGCG G CUACCAGU 4340 ACTGGTAG GGCTAGCTACAACGA CGCTTGTC 5626

4217 AAGCGGCU A CCAGUCCG 4341 CGGACTGG GGCTAGCTACAACGA AGCCGCTT 5627

4221 GGCUACCA G UCCGGAUA 4342 TATCCGGA GGCTAGCTACAACGA TGGTAGCC 5628

4227 CAGUCCGG A UAUCACUC 4343 GAGTGATA GGCTAGCTACAACGA CCGGACTG 5629

4229 GUCCGGAU A UCACUCCG 4344 CGGAGTGA GGCTAGCTACAACGA ATCCGGAC 5630

4232 CGGAUAUC A CUCCGAUG 4345 CATCGGAG GGCTAGCTACAACGA GATATCCG 5631

4238 UCACUCCG A UGACACAG 4346 CTGTGTCA GGCTAGCTACAACGA CGGAGTGA 5632

4241 CUCCGAUG A CACAGACA 4347 TGTCTGTG GGCTAGCTACAACGA CATCGGAG 5633

4243 CCGAUGAC A CAGACACC 4348 GGTGTCTG GGCTAGCTACAACGA GTCATCGG 5634

4247 UGACACAG A CACCACCG 4349 CGGTGGTG GGCTAGCTACAACGA CTGTGTCA 5635

4249 ACACAGAC A CCACCGUG 4350 CACGGTGG GGCTAGCTACAACGA GTCTGTGT 5636

4252 CAGACACC A CCGUGUAC 4351 GTACACGG GGCTAGCTACAACGA GGTGTCTG 5637

4255 ACACCACC G UGUACUCC 4352 GGAGTACA GGCTAGCTACAACGA GGTGGTGT 5638

4257 ACCACCGU G UACUCCAG 4353 CTGGAGTA GGCTAGCTACAACGA ACGGTGGT 5639

4259 CACCGUGU A CUCCAGUG 4354 CACTGGAG GGCTAGCTACAACGA ACACGGTG 5640 4265 GUACUCCA G UGAGGAAG 4355 CTTCCTCA GGCTAGCTACAACGA TGGAGTAC 5641

4273 GUGAGGAA G CAGAACUU 4356 AAGTTCTG GGCTAGCTACAACGA TTCCTCAC 5642

4278 GAAGCAGA A CUUUUAAA 4357 TTTAAAAG GGCTAGCTACAACGA TCTGCTTC 5643

4287 CUUUUAAA G CUGAUAGA 4358 TCTATCAG GGCTAGCTACAACGA TTTAAAAG 5644

4291 UAAAGCUG A UAGAGAUU 4359 AATCTCTA GGCTAGCTACAACGA CAGCTTTA 5645

4297 UGAUAGAG A UUGGAGUG 4360 CACTCCAA GGCTAGCTACAACGA CTCTATCA 5646

4303 AGAUUGGA G UGCAAACC 4361 GGTTTGCA GGCTAGCTACAACGA TCCAATCT 5647

4305 AUUGGAGU G CAAACCGG 4362 CCGGTTTG GGCTAGCTACAACGA ACTCCAAT 5648

4309 GAGUGCAA A CCGGUAGC 4363 GCTACCGG GGCTAGCTACAACGA TTGCACTC 5649

4313 GCAAACCG G UAGCACAG 4364 CTGTGCTA GGCTAGCTACAACGA CGGTTTGC 5650

4316 AACCGGUA G CACAGCCC 4365 GGGCTGTG GGCTAGCTACAACGA TACCGGTT 5651

4318 CCGGUAGC A CAGCCCAG 4366 CTGGGCTG GGCTAGCTACAACGA GCTACCGG 5652

4321 GUAGCACA G CCCAGAUU 4367 AATCTGGG GGCTAGCTACAACGA TGTGCTAC 5653

4327 CAGCCCAG A UUCUCCAG 4368 CTGGAGAA GGCTAGCTACAACGA CTGGGCTG 5654

4335 AUUCUCCA G CCUGACUC 4369 GAGTCAGG GGCTAGCTACAACGA TGGAGAAT 5655

4340 CCAGCCUG A CUCGGGGA 4370 TCCCCGAG GGCTAGCTACAACGA CAGGCTGG 5656

4348 ACUCGGGG A CCACACUG 4371 CAGTGTGG GGCTAGCTACAACGA CCCCGAGT 5657

4351 CGGGGACC A CACUGAGG 4372 GCTCAGTG GGCTAGCTACAACGA GGTCCCCG 5658

4353 GGGACCAC A CUGAGCUC 4373 GAGCTCAG GGCTAGCTACAACGA GTGGTCCC 5659

4358 CACACUGA G CUCUCCUC 4374 GAGGAGAG GGCTAGCTACAACGA TCAGTGTG 5660

4369 CUCCUCCU G UUUAAAAG 4375 CTTTTAAA GGCTAGCTACAACGA AGGAGGAG 5661

4381 AAAAGGAA G CAUCCACA 4376 TGTGGATG GGCTAGCTACAACGA TTCCTTTT 5662

4383 AAGGAAGC A UCCACACC 4377 GGTGTGGA GGCTAGCTACAACGA GCTTCCTT 5663

4387 AAGCAUCC A CACCCCAA 4378 TTGGGGTG GGCTAGCTACAACGA GGATGCTT 5664

4389 GCAUCCAC A CCCCAACU 4379 AGTTGGGG GGCTAGCTACAACGA GTGGATGC 5665

4395 ACACCCCA A CUCCCGGA¹ 4380 TCCGGGAG GGCTAGCTACAACGA TGGGGTGT 5666

4403 ACUCCCGG A CAUCACAU 4381 ATGTGATG GGCTAGCTACAACGA CCGGGAGT 5667

4405 UCCCGGAC A UCACAUGA 4382 TCATGTGA GGCTAGCTACAACGA GTCCGGGA 5668

4408 CGGACAUC A CAUGAGAG 4383 CTCTCATG GGCTAGCTACAACGA GATGTCCG 5669

4410 GACAUCAC A UGAGAGGU 4384 ACCTCTCA GGCTAGCTACAACGA GTGATGTC 5670

4417 CAUGAGAG G UCUGCUCA 4385 TGAGCAGA GGCTAGCTACAACGA CTCTCATG 5671

4421 AGAGGUCU G CUCAGAUU 4386 AATCTGAG GGCTAGCTACAACGA AGACCTCT 5672

4427 CUGCUCAG A UUUUGAAG 4387 CTTCAAAA GGCTAGCTACAACGA CTGAGCAG 5673

4435 AUUUUGAA G UGUUGUUC 4388 GAACAACA GGCTAGCTACAACGA TTCAAAAT 5674

4437 UUUGAAGU G UUGUUCUU 4389 AAGAACAA GGCTAGCTACAACGA ACTTCAAA 5675

4440 GAAGUGUU G UUCUUUCC 4390 GGAAAGAA GGCTAGCTACAACGA AACACTTC 5676

4449 UUCUUUCC A CCAGCAGG 4391 CCTGCTGG GGCTAGCTACAACGA GGAAAGAA 5677

4453 UUCCACCA G CAGGAAGU 4392 ACTTCCTG GGCTAGCTACAACGA TGGTGGAA 5678

4460 AGCAGGAA G UAGCCGCA 4393 TGCGGCTA GGCTAGCTACAACGA TTCCTGCT 5679

4463 AGGAAGUA G CCGCAUUU 4394 AAATGCGG GGCTAGCTACAACGA TACTTCCT 5680

4466 AAGUAGCC G CAUUUGAU 4395 ATCAAATG GGCTAGCTACAACGA GGCTACTT 5681

4468 GUAGCCGC A UUUGAUUU 4396 AAATCAAA GGCTAGCTACAACGA GCGGCTAC 5682

4473 CGCAUUUG A UUUUCAUU 4397 AATGAAAA GGCTAGCTACAACGA CAAATGCG 5683

4479 UGAUUUUG A UUUCGACA 4398 TGTCGAAA GGCTAGCTACAACGA GAAAATCA 5684

4485 UCAUUUCG A CAACAGAA 4399 TTCTGTTG GGCTAGCTACAACGA CGAAATGA 5685

4488 UUUCGACA A CAGAAAAA 4400 TTTTTCTG GGCTAGCTACAACGA TGTCGAAA 5686

4499 GAAAAAGG A CCUCGGAC 4401 GTCCGAGG GGCTAGCTACAACGA CCTTTTTC 5687

4506 GACCUCGG A CUGCAGGG 4402 CCCTGCAG GGCTAGCTACAACGA CCGAGGTC 5688

4509 CUCGGACU G CAGGGAGC 4403 GCTCCCTG GGCTAGCTACAACGA AGTCCGAG 5689

4516 UGCAGGGA G CCAGUCUU 4404 AAGACTGG GGCTAGCTACAACGA TCCCTGCA 5690

4520 GGGAGCCA G UCUUCUAG 4405 CTAGAAGA GGCTAGCTACAACGA TGGCTCCC 5691

4529 UCUUCUAG G CAUAUCCU 4406 AGGATATG GGCTAGCTACAACGA CTAGAAGA 5692

4531 UUCUAGGC A UAUCCUGG 4407 CCAGGATA GGCTAGCTACAACGA GCCTAGAA 5693 4533 CUAGGCAU A UCCUGGAA 4408 TTCCAGGA GGCTAGCTACAACGA ATGCCTAG 5694

4545 UGGAAGAG G CUUGUGAC 4409 GTCACAAG GGCTAGCTACAACGA CTCTTCCA 5695

4549 AGAGGCUU G UGACCCAA 4410 TTGGGTCA GGCTAGCTACAACGA AAGCCTCT 5696

4552 GGCUUGUG A CCCAAGAA 4411 TTCTTGGG GGCTAGCTACAACGA CACAAGCC 5697

4560 ACCCAAGA A UGUGUCUG 4412 CAGACACA GGCTAGCTACAACGA TCTTGGGT 5698

4562 CCAAGAAU G UGUCUGUG 4413 CACAGACA GGCTAGCTACAACGA ATTCTTGG 5699

4564 AAGAAUGU G UCUGUGUC 4414 GACACAGA GGCTAGCTACAACGA ACATTCTT 5700

4568 AUGUGUCU G UGUCUUCU 4415 AGAAGACA GGCTAGCTACAACGA AGACACAT 5701

4570 GUGUCUGU G UCUUCUCC 4416 GGAGAAGA GGCTAGCTACAACGA ACAGACAC 5702

4581 UUCUCCCA G UGUUGACC 4417 GGTCAACA GGCTAGCTACAACGA TGGGAGAA 5703

4583 CUCCCAGU G UUGACCUG 4418 CAGGTCAA GGCTAGCTACAACGA ACTGGGAG 5704

4587 CAGUGUUG A CCUGAUCC 4419 GGATCAGG GGCTAGCTACAACGA CAACACTG 5705

4592 UUGACCUG A UCCUCUUU 4420 AAAGAGGA GGCTAGCTACAACGA CAGGTCAA 5706

4605 CUUUUUUC A UUCAUUUA 4421 TAAATGAA GGCTAGCTACAACGA GAAAAAAG 5707

4609 UUUCAUUC A UUUAAAAA 4422 TTTTTAAA GGCTAGCTACAACGA GAATGAAA 5708

4618 UUUAAAAA G CAUUAUCA 4423 TGATAATG GGCTAGCTACAACGA TTTTTAAA 5709

4620 UAAAAAGC A UUAUCAUG 4424 CATGATAA GGCTAGCTACAACGA GCTTTTTA 5710

4623 AAAGCAUU A UCAUGCCC 4425 GGGCATGA GGCTAGCTACAACGA AATGCTTT 5711

4626 GCAUUAUC A UGCCCCUG 4426 CAGGGGCA GGCTAGCTACAACGA GATAATGC 5712

4628 AUUAUCAU G CCCCUGCU 4427 AGCAGGGG GGCTAGCTACAACGA ATGATAAT 5713

4634 AUGCCCCU G CUGCGGGU 4428 ACCCGCAG GGCTAGCTACAACGA AGGGGCAT 5714

4637 CCCCUGCU G CGGGUCUC 4429 GAGACCCG GGCTAGCTACAACGA AGCAGGGG 5715

4641 UGCUGCGG G UCUCACCA 4430 TGGTGAGA GGCTAGCTACAACGA CCGCAGCA 5716

4646 CGGGUCUC A CCAUGGGU 4431 ACCCATGG GGCTAGCTACAACGA GAGACCCG 5717

4649 GUCUCACC A UGGGUUUA 4432 TAAACCCA GGCTAGCTACAACGA GGTGAGAC 5718

4653 CACCAUGG G UUUAGAAC 4433 GTTCTAAA GGCTAGCTACAACGA CCATGGTG 5719

4660 GGUUUAGA A CAAAGAGC 4434 GCTCTTTG GGCTAGCTACAACGA TCTAAACC 5720

4667 AACAAAGA G CUUCAAGC 4435 GCTTGAAG GGCTAGCTACAACGA TCTTTGTT 5721

4674 AGCUUCAA G CAAUGGCC 4436 GGCCATTG GGCTAGCTACAACGA TTGAAGCT 5722

4677 UUCAAGCA A UGGCCCCA 4437 TGGGGCCA GGCTAGCTACAACGA TGCTTGAA 5723

4680 AAGCAAUG G CCCCAUCC 4438 GGATGGGG GGCTAGCTACAACGA CATTGCTT 5724

4685 AVGGCCCC A UCCUCAAA 4439 TTTGAGGA GGCTAGCTACAACGA GGGGCCAT 5725

4697 UCAAAGAA G UAGCAGUA 4440 TACTGCTA GGCTAGCTACAACGA TTCTTTGA 5726

4700 AAGAAGUA G CAGUACCU 4441 AGGTACTG GGCTAGCTACAACGA TACTTCTT 5727

4703 AAGUAGCA G UACCUGGG 4442 CCCAGGTA GGCTAGCTACAACGA TGCTACTT 5728

4705 GUAGCAGU A CCUGGGGA 4443 TCCCCAGG GGCTAGCTACAACGA ACTGCTAC 5729

4714 CCUGGGGA G CUGACACU 4444 AGTGTCAG GGCTAGCTACAACGA TCCCCAGG 5730

4718 GGGAGCUG A CACUUCUG 4445 CAGAAGTG GGCTAGCTACAACGA CAGCTCCC 5731

4720 GAGCUGAC A CUUCUGUA 4446 TACAGAAG GGCTAGCTACAACGA GTCAGCTC 5732

4726 ACACUUCU G UAAAACUA 4447 TAGTTTTA GGCTAGCTACAACGA AGAAGTGT 5733

4731 UCUGUAAA A CUAGAAGA 4448 TCTTCTAG GGCTAGCTACAACGA TTTACAGA 5734

4739 ACUAGAAG A UAAACCAG 4449 CTGGTTTA GGCTAGCTACAACGA CTTCTAGT 5735

4743 GAAGAUAA A CCAGGCAA 4450 TTGCCTGG GGCTAGCTACAACGA TTATCTTC 5736

4748 UAAACCAG G CAACGUAA 4451 TTACGTTG GGCTAGCTACAACGA CTGGTTTA 5737

4751 ACCAGGCA A CGUAAGUG 4452 CACTTACG GGCTAGCTACAACGA TGCCTGGT 5738

4753 CAGGCAAC G UAAGUGUU 4453 AACACTTA GGCTAGCTACAACGA GTTGCCTG 5739

4757 CAACGUAA G UGUUCGAG 4454 CTCGAACA GGCTAGCTACAACGA TTACGTTG 5740

4759 ACGUAAGU G UUCGAGGU 4455 ACCTCGAA GGCTAGCTACAACGA ACTTACGT 5741

4766 UGUUCGAG G UGUUGAAG 4456 CTTGAACA GGCTAGCTACAACGA CTCGAACA 5742

4768 UUCGAGGU G UUGAAGAU 4457 ATCTTCAA GGCTAGCTACAACGA ACCTCGAA 5743

4775 UGUUGAAG A UGGGAAGG 4458 CCTTCCCA GGCTAGCTACAACGA CTTCAACA 5744

4784 UGGGAAGG A UUUGCAGG 4459 CCTGCAAA GGCTAGCTACAACGA CCTTCCCA 5745

4788 AAGGAUUU G CAGGGCUG 4460 CAGCCCTG GGCTAGCTACAACGA AAATCCTT 5746 4793 UUUGCAGG G CUGAGUCU 4461 AGACTCAG GGCTAGCTACAACGA CCTGCAAA 5747

4798 AGGGCUGA G UCUAUCCA 4462 TGGATAGA GGCTAGCTACAACGA TCAGCCCT 5748

4802 CUGAGUCU A UCCAAGAG 4463 CTCTTGGA GGCTAGCTACAACGA AGACTCAG 5749

4811 UCCAAGAG G CUUUGUUU 4464 AAACAAAG GGCTAGCTACAACGA CTCTTGGA 5750

4816 GAGGCUUU G UUUAGGAC 4465 GTCCTAAA GGCTAGCTACAACGA AAAGCCTC 5751

4823 UGUUUAGG A CGUGGGUC 4466 GACCCACG GGCTAGCTACAACGA CCTAAACA 5752

4825 UUUAGGAC G UGGGUCCC 4467 GGGACCCA GGCTAGCTACAACGA GTCCTAAA 5753

4829 GGACGUGG G UCCCAAGC 4468 GCTTGGGA GGCTAGCTACAACGA CCACGTCC 5754

4836 GGUCCCAA G CCAAGCCU 4469 AGGCTTGG GGCTAGCTACAACGA TTGGGACC 5755

4841 CAAGCCAA G CCUUAAGU 4470 AGTTAAGG GGCTAGCTACAACGA TTGGCTTG 5756

4848 AGCCUUAA G UGUGGAAU 4471 ATTCCACA GGCTAGCTACAACGA TTAAGGCT 5757

4850 CCUUAAGU G UGGAAUUC 4472 GAATTCCA GGCTAGCTACAACGA ACTTAAGG 5758

4855 AGUGUGGA A UUCGGAUU 4473 AATCCGAA GGCTAGCTACAACGA TCCACACT 5759

4861 GAAUUCGG A UUGAUAGA 4474 TCTATCAA GGCTAGCTACAACGA CCGAATTC 5760

4865 UCGGAUUG A UAGAAAGG 4475 CCTTTCTA GGCTAGCTACAACGA CAATCCGA 5761

4877 AAAGGAAG A CUAACGUU 4476 AACGTTAG GGCTAGCTACAACGA CTTCCTTT 5762

4881 GAAGACUA A CGUUACCU 4477 AGGTAACG GGCTAGCTACAACGA TAGTCTTC 5763

4883 AGACUAAC G UUACCUUG 4478 CAAGGTAA GGCTAGCTACAACGA GTTAGTCT 5764

4886 CUAACGUU A CCUUGGUU 4479 AAGCAAGG GGCTAGCTACAACGA AACGTTAG 5765

4891 GUUACCUU G CUUUGGAG 4480 CTCCAAAG GGCTAGCTACAACGA AAGGTAAC 5766

4901 UUUGGAGA G UACUGGAG 4481 CTCCAGTA GGCTAGCTACAACGA TCTCCAAA 5767

4903 UGGAGAGU A CUGGAGCC 4482 GGCTCCAG GGCTAGCTACAACGA ACTCTCCA 5768

4909 GUACUGGA G CCUGCAAA 4483 TTTGCAGG GGCTAGCTACAACGA TCCAGTAC 5769

4913 UGGAGCCU G CAAAUGCA 4484 TGCATTTG GGCTAGCTACAACGA AGGCTCCA 5770

4917 GCCUGCAA A UGCAUUGU 4485 ACAATGCA GGCTAGCTACAACGA TTGCAGGC 5771

4919 CUGCAAAU G CAUUGUGU 4486 ACACAATG GGCTAGCTACAACGA ATTTGCAG 5772

4921 GCAAAUGC A UUGUGUUU 4487 AAACACAA GGCTAGCTACAACGA GCATTTGC 5773

4924 AAUGCAUU G UGUUUGCU 4488 AGCAAACA GGCTAGCTACAACGA AATGCATT 5774

4926 UGCAUUGU G UUUGCUCU 4489 AGAGCAAA GGCTAGCTACAACGA ACAATGCA 5775

4930 UUGUGUUU G CUGUGGUG 4490 CACCAGAG GGCTAGCTACAACGA AAACACAA 5776

4936 UUGCUCUG G UGGAGGUG 4491 CACCTCCA GGCTAGCTACAACGA CAGAGCAA 5777

4942 UGGUGGAG G UGGGCAUG 4492 CATGCCCA GGCTAGCTACAACGA CTCCACCA 5778

4946 GGAGGUGG G CAUGGGGU 4493 ACCCCATG GGCTAGCTACAACGA CCACCTCC 5779

4948 AGGUGGGC A UGGGGUCU 4494 AGACCCCA GGCTAGCTACAACGA GCCCACCT 5780

4953 GGCAUGGG G UCUGUUCU 4495 AGAACAGA GGCTAGCTACAACGA CCCATGCC 5781

4957 UGGGGUCU G UUCUGAAA 4496 TTTCAGAA GGCTAGCTACAACGA AGACCCCA 5782

4965¹ GUUCUGAA A UGUAAAGG 4497 CCTTTACA GGCTAGCTACAACGA TTCAGAAC 5783

4967 UCUGAAAU G UAAAGGGU 4498 ACCCTTTA GGCTAGCTACAACGA ATTTCAGA 5784

4974 UGUAAAGG G UUCAGACG 4499 CGTCTGAA GGCTAGCTACAACGA CCTTTACA 5785

4980 GGGUUCAG A CGGGGUUU 4500 AAACCCCG GGCTAGCTACAACGA CTGAACCC 5786

4985 CAGACGGG G UUUCUGGU 4501 ACCAGAAA GGCTAGCTACAACGA CCCGTCTG 5787

4992 GGUUUCUG G UUUUAGAA 4502 TTCTAAAA GGCTAGCTACAACGA CAGAAACC 5788

5002 UUUAGAAG G UUGCGUGU 4503 ACACGCAA GGCTAGCTACAACGA CTTCTAAA 5789

5005 AGAAGGUU G CGUGUUCU 4504 AGAACACG GGCTAGCTACAACGA AACCTTCT 5790

5007 AAGGUUGC G UGUUCUUC 4505 GAAGAACA GGCTAGCTACAACGA GCAACCTT 5791

5009 GGUUGCGU G UUCUUCGA 4506 TCGAAGAA GGCTAGCTACAACGA ACGCAACC 5792

5018 UUCUUCGA G UUGGGCUA 4507 TAGCCCAA GGCTAGCTACAACGA TCGAAGAA 5793

5023 CGAGUUGG G CUAAAGUA 4508 TACTTTAG GGCTAGCTACAACGA CCAACTCG 5794

5029 GGGCUAAA G UAGAGUUC 4509 GAACTCTA GGCTAGCTACAACGA TTTAGCCC 5795

5034 AAAGUAGA G UUCGUUGU 4510 ACAACGAA GGCTAGCTACAACGA TCTACTTT 5796

5038 UAGAGUUC G UUGUGCUG 4511 CAGCACAA GGCTAGCTACAACGA GAACTCTA 5797

5041 AGUUCGUU G UGCUGUUU 4512 AAACAGCA GGCTAGCTACAACGA AACGAACT 5798

5043 UUCGUUGU G CUGUUUCU 4513 AGAAACAG GGCTAGCTACAACGA ACAACGAA 5799 5046 GUUGUGCU G UUUCUGAG 4514 GTCAGAAA GGCTAGCTACAACGA AGCACAAC 5800

5053 UGUUUCUG A CUCCUAAU 4515 ATTAGGAG GGCTAGCTACAACGA CAGAAACA 5801

5060 GACUCCUA A UGAGAGUU 4516 AACTCTCA GGCTAGCTACAACGA TAGGAGTC 5802

5066 UAAUGAGA G UUCCUUCC 4517 GGAAGGAA GGCTAGCTACAACGA TCTCATTA 5803

5077 CCUUCCAG A CCGUUAGC 4518 GCTAACGG GGCTAGCTACAACGA CTGGAAGG 5804

5080 UCCAGACC G UUAGCUGU 4519 ACAGCTAA GGCTAGCTACAACGA GGTCTGGA 5805

5084 GACCGUUA G CUGUCUCC 4520 GGAGACAG GGCTAGCTACAACGA TAACGGTC 5806

5087 CGUUAGCU G UCUCCUUG 4521 CAAGGAGA GGCTAGCTACAACGA AGCTAACG 5807

5095 GUCUCCUU G CCAAGCCC 4522 GGGCTTGG GGCTAGCTACAACGA AAGGAGAC 5808

5100 CUUGCCAA G CCCCAGGA 4523 TCCTGGGG GGCTAGCTACAACGA TTGGCAAG 5809

5114 GGAAGAAA A UGAUGCAG 4524 CTGCATCA GGCTAGCTACAACGA TTTCTTCC 5810

5117 AGAAAAUG A UGCAGCUC 4525 GAGCTGCA GGCTAGCTACAACGA CATTTTCT 5811

5119 AAAAUGAU G CAGCUCUG 4526 CAGAGCTG GGCTAGCTACAACGA ATCATTTT 5812

5122 AUGAUGCA G CUCUGGCU 4527 AGCCAGAG GGCTAGCTACAACGA TGCATCAT 5813

5128 CAGCUCUG G CUCCUUGU 4528 ACAAGGAG GGCTAGCTACAACGA CAGAGCTG 5814

5135 GGCUCCUU G UCUCCCAG 4529 CTGGGAGA GGCTAGCTACAACGA AAGGAGCC 5815

5144 UCUCCCAG G CUGAUCCU 4530 AGGATCAG GGCTAGCTACAACGA CTGGGAGA 5816

5148 CCAGGCUG A UCCUUUAU 4531 ATAAAGGA GGCTAGCTACAACGA CAGCCTGG 5817

5155 GAUCCUUU A UUCAGAAU 4532 ATTCTGAA GGCTAGCTACAACGA AAAGGATC 5818

5162 UAUUCAGA A UACCACAA 4533 TTGTGGTA GGCTAGCTACAACGA TCTGAATA 5819

5164 UUCAGAAU A CCACAAAG 4534 CTTTGTGG GGCTAGCTACAACGA ATTCTGAA 5820

5167 AGAAUACC A CAAAGAAA 4535 TTTCTTTG GGCTAGCTACAACGA GGTATTCT 5821

5178 AAGAAAGG A CAUUCAGC 4536 GCTGAATG GGCTAGCTACAACGA CCTTTCTT 5822

5180 GAAAGGAC A UUCAGCUC 4537 GAGCTGAA GGCTAGCTACAACGA GTCCTTTC 5823

5185 GACAUUCA G CUCAAGGC 4538 GCCTTGAG GGCTAGCTACAACGA TGAATGTC 5824

5192 AGCUCAAG G CUCCCUGC 4539 GCAGGGAG GGCTAGCTACAACGA CTTGAGCT 5825

5199 GGCUCCCU G CCGUGUUG 4540 CAACACGG GGCTAGCTACAACGA AGGGAGCC 5826

5202 UCCCUGCC G UGUUGAAG 4541 CTTCAACA GGCTAGCTACAACGA GGCAGGGA 5827

5204 CCUGCCGU G UUGAAGAG 4542 CTCTTCAA GGCTAGCTACAACGA ACGGCAGG 5828

5212 GUUGAAGA G UUCUGACU 4543 AGTCAGAA GGCTAGCTACAACGA TCTTCAAC 5829

5218 GAGUUCUG A CUGCACAA 4544 TTGTGCAG GGCTAGCTACAACGA CAGAACTC 5830

5221 UUCUGACU G CACAAACC 4545 GGTTTGTG GGCTAGCTACAACGA AGTCAGAA 5831

5223 CUGACUGC A CAAACCAG 4546 CTGGTTTG GGCTAGCTACAACGA GCAGTCAG 5832

5227 CUGCACAA A CCAGCUUC 4547 GAAGCTGG GGCTAGCTACAACGA TTGTGCAG 5833

5231 ACAAACCA G CUUCUGGU 4548 ACCAGAAG GGCTAGCTACAACGA TGGTTTGT 5834

5238 AGCUUCUG G UUUCUUCU 4549 AGAAGAAA GGCTAGCTACAACGA CAGAAGCT 5835

5250 CUUCUGGA A UGAAUACC 4550 GGTATTCA GGCTAGCTACAACGA TCCAGAAG 5836

5254 UGGAAUGA A UACCCUCA 4551 TGAGGGTA GGCTAGCTACAACGA TCATTCCA 5837

5256 GAAUGAAU A CCCUCAUA 4552 TATGAGGG GGCTAGCTACAACGA ATTCATTC 5838

5262 AUACCCUC A UAUCUGUC 4553 GACAGATA GGCTAGCTACAACGA GAGGGTAT 5839

5264 ACCCUCAU A UCUGUCCU 4554 AGGACAGA GGCTAGCTACAACGA ATGAGGGT 5840

5268 UCAUAUCU G UCCUGAUG 4555 CATCAGGA GGCTAGCTACAACGA AGATATGA 5841

5274 CUGUCCUG A UGUGAUAU 4556 ATATCACA GGCTAGCTACAACGA CAGGACAG 5842

5276 GUCCUGAU G UGAUAUGU 4557 ACATATCA GGCTAGCTACAACGA ATCAGGAC 5843

5279 CUGAUGUG A UAUGUCUG 4558 CAGACATA GGCTAGCTACAACGA CACATCAG 5844

5281 GAUGUGAU A UGUCUGAG 4559 CTCAGACA GGCTAGCTACAACGA ATCACATC 5845

5283 UGUGAUAU G UCUGAGAC 4560 GTCTCAGA GGCTAGCTACAACGA ATATCACA 5846

5290 UGUCUGAG A CUGAAUGC 4561 GCATTCAG GGCTAGCTACAACGA CTCAGACA 5847

5295 GAGACUGA A UGCGGGAG 4562 CTCCCGCA GGCTAGCTACAACGA TCAGTCTC 5848

5297 GACUGAAU G CGGGAGGU 4563 ACCTCCCG GGCTAGCTACAACGA ATTCAGTC 5849

5304 UGCGGGAG G UUCAAUGU 4564 ACATTGAA GGCTAGCTACAACGA CTCCCGCA 5850

5309 GAGGUUCA A UGUGAAGC 4565 GCTTCACA GGCTAGCTACAACGA TGAACCTC 5851

5311 GGUUCAAU G UGAAGCUG 4566 CAGCTTCA GGCTAGCTACAACGA ATTGAACC 5852 5316 AAUGUGAA G CUGUGUGU 4567 ACACACAG GGCTAGCTACAACGA TTCACATT 5853

5319 GUGAAGCU G UGUGUGGU 4568 ACCACACA GGCTAGCTACAACGA AGCTTCAC 5854

5321 GAAGCUGU G UGUGGUGU 4569 ACACCACA GGCTAGCTACAACGA ACAGCTTC 5855

5323 AGCUGUGU G UGGUGUCA 4570 TGACACCA GGCTAGCTACAACGA ACACAGCT 5856

5326 UGUGUGUG G UGUCAAAG 4571 CTTTGACA GGCTAGCTACAACGA CACACACA 5857

5328 UGUGUGGU G UGAAAGUU 4572 AACTTTGA GGCTAGCTACAACGA ACCACACA 5858

5334 GUGUCAAA G UUUCAGGA 4573 TCCTGAAA GGCTAGCTACAACGA TTTGACAC 5859

5346 CAGGAAGG A UUUUACCC 4574 GGGTAAAA GGCTAGCTACAACGA CCTTCCTG 5860

5351 AGGAUUUU A CCCUUUUG 4575 CAAAAGGG GGCTAGCTACAACGA AAAATCCT 5861

5359 ACCCUUUU G UUCUUCCG 4576 GGGAAGAA GGCTAGCTACAACGA AAAAGGGT 5862

5371 UUCCCCCU G UCCCCAAC 4577 GTTGGGGA GGCTAGCTACAACGA AGGGGGAA 5863

5378 UGUCCCCA A CCCACUCU 4578 AGAGTGGG GGCTAGCTACAACGA TGGGGACA 5864

5382 CCCAACCC A CUCUCACC 4579 GGTGAGAG GGCTAGCTACAACGA GGGTTGGG 5865

5388 CCACUCUC A CCCCGCAA 4580 TTGCGGGG GGCTAGCTACAACGA GAGAGTGG 5866

5393 CUCΆCCCC G CAACCCAU 4581 ATGGGTTG GGCTAGCTACAACGA GGGGTGAG 5867

5396 ACCCCGCA A CCCAUCAG 4582 CTGATGGG GGCTAGCTACAACGA TGCGGGGT 5868

5400 CGCAACCC A UCAGUAUU 4583 AATACTGA GGCTAGCTACAACGA GGGTTGCG 5869

5404 ACCCAUCA G UAUUUUAG 4584 CTAAAATA GGCTAGCTACAACGA TGATGGGT 5870

5406 CCAUCAGU A UUUUAGUU 4585 AACTAAAA GGCTAGCTACAACGA AGTGATGG 5871

5412 GUAUUUUA G UUAUUUGG 4586 CCAAATAA GGCTAGCTACAACGA TAAAATAC 5872

5415 UUUUAGUU A UUUGGCCU 4587 AGGCCAAA GGCTAGCTACAACGA AACTAAAA 5873

5420 GUUAUUUG G CCUCUACU 4588 AGTAGAGG GGCTAGCTACAACGA CAAATAAC 5874

5426 UGGCCUCU A CUCCAGUA 4589 TACTGGAG GGCTAGCTACAACGA AGAGGCCA 5875

5432 CUACUCCA G UAAACCUG 4590 CAGGTTTA GGCTAGCTACAACGA TGGAGTAG 5876

5436 UCCAGUAA A CCUGAUUG 4591 CAATCAGG GGCTAGCTACAACGA TTACTGGA 5877

5441 UAAACCUG A UUGGGUUU 4592 AAACCCAA GGCTAGCTACAACGA CAGGTTTA 5878

5446 CUGAUUGG G UUUGUUCA 4593 TGAACAAA GGCTAGCTACAACGA CCAATCAG 5879

5450 UUGGGUUU G UUCACUCU 4594 AGAGTGAA GGCTAGCTACAACGA AAACCCAA 5880

5454 GUUUGUUC A CUCUCUGA 4595 TCAGAGAG GGCTAGCTACAACGA GAACAAAC 5881

5463 CUCUCUGA A UGAUUAUU 4596 AATAATCA GGCTAGCTACAACGA TCAGAGAG 5882

5466 UCUGAAUG A UUAUUAGC 4597 GCTAATAA GGCTAGCTACAACGA CATTCAGA 5883

5469 GAAUGAUU A UUAGCCAG 4598 CTGGCTAA GGCTAGCTACAACGA AATCATTC 5884

5473 GAUUAUUA G CCAGACUU 4599 AAGTCTGG GGCTAGCTACAACGA TAATAATC 5885

5478 UUAGCCAG A CUUCAAAA 4600 TTTTGAAG GGCTAGCTACAACGA CTGGCTAA 5886

5486 ACUUCAAA A UUAUUUUA 4601 TAAAATAA GGCTAGCTACAACGA TTTGAAGT 5887

5489 UCAAAAUU A UUUUAUAG 4602 CTATAAAA GGCTAGCTACAACGA AATTTTGA 5888

5494 AUUAUUUU A UAGCCCAA 4603 TTGGGCTA GGCTAGCTACAACGA AAAATAAT 5889

5497 AUUUUAUA G CCCAAAUU 4604 AATTTGGG GGCTAGCTACAACGA TATAAAAT 5890

5503 UAGCCCAA A UUAUAACA 4605 TGTTATAA GGCTAGCTACAACGA TTGGGCTA 5891

5506 CCCAAAUU A UAACAUCU 4606 AGATGTTA GGCTAGCTACAACGA AATTTGGG 5892

5509 AAAUUAUA A CAUCUAUU 4607 AATAGATG GGCTAGCTACAACGA TATAATTT 5893

5511 AUUAUAAC A UCUAUUGU 4608 ACAATAGA GGCTAGCTACAACGA GTTATAAT 5894

5515 UAACAUCU A UUGUAUUA 4609 TAATACAA GGCTAGCTACAACGA AGATGTTA 5895

5518 CAUCUAUU G UAUUAUUU 4610 AAATAATA GGCTAGCTACAACGA AATAGATG 5896

5520 UCUAUUGU A UUAUUUAG 4611 CTAAATAA GGCTAGCTACAACGA ACAATAGA 5897

5523 AUUGUAUU A UUUAGACU 4612 AGTCTAAA GGCTAGCTACAACGA AATACAAT 5898

5529 UUAUUUAG A CUUUUAAC 4613 GTTAAAAG GGCTAGCTACAACGA CTAAATAA 5899

5536 GACUUUUA A CAUAUAGA 4614 TCTATATG GGCTAGCTACAACGA TAAAAGTC 5900

5538 CUUUUAAC A UAUAGAGC 4615 GCTCTATA GGCTAGCTACAACGA GTTAAAAG 5901

5540 UUUAACAU A UAGAGCUA 4616 TAGCTCTA GGCTAGCTACAACGA ATGTTAAA 5902

5545 CAUAUAGA G CUAUUUCU 4617 AGAAATAG GGCTAGCTACAACGA TCTATATG 5903

5548 AUAGAGCU A UUUCUACU 4618 AGTAGAAA GGCTAGCTACAACGA AGCTCTAT 5904

5554 CUAUUUCU A CUGAUUUU 4619 AAAATCAG GGCTAGCTACAACGA AGAAATAG 5905 5558 UUCUACUG A UUUUUGCC 4620 GGCAAAAA GGCTAGCTACAACGA CAGTAGAA 5906

5564 UGAUUUUU G CCCUUGUU 4621 AACAAGGG GGCTAGCTACAACGA AAAAATCA 5907

5570 UUGCCCUU G UUCUGUCC 4622 GGACAGAA GGCTAGCTACAACGA AAGGGCAA 5908

5575 CUUGUUCU G UGCUUUUU 4623 AAAAAGGA GGCTAGCTACAACGA AGAACAAG 5909

5597 AAAAGAAA A UGUGUUUU 4624 AAAACACA GGCTAGCTACAACGA TTTCTTTT 5910

5599 AAGAAAAU G UGUUUUUU 4625 AAAAAACA GGCTAGCTACAACGA ATTTTCTT 5911

5601 GAAAAUGU G UUUUUUGU 4626 ACAAAAAA GGCTAGCTACAACGA ACATTTTC 5912

5608 UGUUUUUU G UUUGGUAC 4627 GTACCAAA GGCTAGCTACAACGA AAAAAACA 5913

5613 UUUGUUUG G UACCAUAG 4628 CTATGGTA GGCTAGCTACAACGA CAAACAAA 5914

5615 UGUUUGGU A CCAUAGUG 4629 CAGTATGG GGCTAGCTACAACGA ACCAAACA 5915

5618 UUGGUACC A UAGUGUGA 4630 TCACACTA GGCTAGCTACAACGA GGTACCAA 5916

5621 GUACCAUA G UGUGAAAU 4631 ATTTCACA GGCTAGCTACAACGA TATGGTAC 5917

5623 ACCAUAGU G UGAAAUGC 4632 GCATTTCA GGCTAGCTACAACGA ACTATGGT 5918

5628 AGUGUGAA A UGCUGGGA 4633 TCCCAGCA GGCTAGCTACAACGA TTCACACT 5919

5630 UGUGAAAU G CUGGGAAC 4634 GTTCCCAG GGCTAGCTACAACGA ATTTCACA 5920

5637 UGCUGGGA A CAAUGACU 4635 AGTCATTG GGCTAGCTACAACGA TCCCAGCA 5921

5640 UGGGAACA A UGACUAUA 4636 TATAGTCA GGCTAGCTACAACGA TGTTCCCA 5922

5643 GAACAAUG A CUAUAAGA 4637 TCTTATAG GGCTAGCTACAACGA CATTGTTC 5923

5646 CAAUGACU A UAAGACAU 4638 ATGTCTTA GGCTAGCTACAACGA AGTCATTG 5924

5651 ACUAUAAG A CAUGCUAU 4639 ATAGCATG GGCTAGCTACAACGA CTTATAGT 5925

5653 UAUAAGAC A UGCUAUGG 4640 CCATAGCA GGCTAGCTACAACGA GTCTTATA 5926

5655 UAAGACAU G CUAUGGCA 4641 TGCCATAG GGCTAGCTACAACGA ATGTCTTA 5927

5658 GACAUGCU A UGGCACAU 4642 ATGTGCCA GGCTAGCTACAACGA AGCATGTC 5928

5661 AUGCUAUG G CACAUAUA 4643 TATATGTG GGCTAGCTACAACGA CATAGCAT 5929

5663 GCUAUGGC A CAUAUAUU 4644 AATATATG GGCTAGCTACAACGA GCCATAGC 5930

5665 UAUGGCAC A UAUAUUUA 4645 TAAATATA GGCTAGCTACAACGA GTGCCATA 5931

5667 UGGCACAU A UAUUUAUA 4646 TATAAATA GGCTAGCTACAACGA ATGTGCCA 5932

5669 GCACAUAU A UUUAUAGU 4647 ACTATAAA GGCTAGCTACAACGA ATATGTGC 5933

5673 AUAUAUUU A UAGUCUGU 4648 ACAGACTA GGCTAGCTACAACGA AAATATAT 5934

5676 UAUUUAUA G UCUGUUUA 4649 TAAACAGA GGCTAGCTACAACGA TATAAATA 5935

5680 UAUAGUCU G UUUAUGUA 4650 ^' TACATAAA GGCTAGCTACAACGA AGACTATA 5936

5684 GUCUGUUU A UGUAGAAA 4651 TTTCTACA GGCTAGCTACAACGA AAACAGAC 5937

5686 CUGUUUAU G UAGAAACA 4652 TGTTTCTA GGCTAGCTACAACGA ATAAACAG 5938

5692 AUGUAGAA A CAAAUGUA 4653 TACATTTG GGCTAGCTACAACGA TTCTACAT 5939

5696 AGAAACAA A UGUAAUAU 4654 ATATTACA GGCTAGCTACAACGA TTGTTTCT 5940

5698 AAACAAAU G UAAUAUAU 4655 ATATATTA GGCTAGCTACAACGA ATTTGTTT 5941

5701 CAAAUGUA A UAUAUUAA 4656 TTAATATA GGCTAGCTACAACGA TACATTTG 5942

5703 AAUGUAAU A UAUUAAAG 4657 CTTTAATA GGCTAGCTACAACGA ATTACATT 5943

5705 UGUAAUAU A UUAAAGCC 4658 GGCTTTAA GGCTAGCTACAACGA ATATTACA 5944

5711 AUAUUAAA G CCUUAUAU 4659 ATATAAGG GGCTAGCTACAACGA TTTAATAT 5945

5716 AAAGCCUU A UAUAUAAU 4660 ATTATATA GGCTAGCTACAACGA AAGGCTTT 5946

5718 AGCCUUAU A UAUAAUGA 4661 TCATTATA GGCTAGCTACAACGA ATAAGGCT 5947

5720 CCUUAUAU A UAAUGAAC 4662 GTTCATTA GGCTAGCTACAACGA ATATAAGG 5948

5723 UAUAUAUA A UGAACUUU 4663 AAAGTTCA GGCTAGCTACAACGA TATATATA 5949

5727 UAUAAUGA A CUUUGUAC 4664 GTACAAAG GGCTAGCTACAACGA TCATTATA 5950

5732 UGAACUUU G UACUAUUC 4665 GAATAGTA GGCTAGCTACAACGA AAAGTTCA 5951

5734 AACUUUGU A CUAUUCAC 4666 GTGAATAG GGCTAGCTACAACGA ACAAAGTT 5952

5737 UUUGUACU A UUCACAUU 4667 AATGTGAA GGCTAGCTACAACGA AGTACAAA 5953

5741 UACUAUUC A CAUUUUGU 4668 ACAAAATG GGCTAGCTACAACGA GAATAGTA 5954

5743 CUAUUCAC A UUUUGUAU 4669 ATACAAAA GGCTAGCTACAACGA GTGAATAG 5955

5748 CACAUUUU G UAUCAGUA 4670 TACTGATA GGCTAGCTACAACGA AAAATGTG 5956

5750 CAUUUUGU A UCAGUAUU 4671 AATACTGA GGCTAGCTACAACGA ACAAAATG 5957

5754 UUGUAUCA G UAUUAUGU 4672 ACATAATA GGCTAGCTACAACGA TGATACAA 5958 5756 GUAUCAGU A UUAUGUAG 4673 CTACATAA GGCTAGCTACAACGA ACTGATAC 5959

5759 UCAGUAUU A UGUAGCAU 4674 ATGCTACA GGCTAGCTACAACGA AATACTGA 5960

5761 AGUAUUAU G UAGCAUAA 4675 TTATGCTA GGCTAGCTACAACGA ATAATACT 5961

5764 AUUAUGUA G CAUAACAA 4676 TTGTTATG GGCTAGCTACAACGA TACATAAT 5962

5766 UAUGUAGC A UAACAAAG 4677 CTTTGTTA GGCTAGCTACAACGA GCTACATA 5963

5769 GUAGCAUA A CAAAGGUC 4678 GACCTTTG GGCTAGCTACAACGA TATGCTAC 5964

5775 UAACAAAG G UCAUAAUG 4679 CATTATGA GGCTAGCTACAACGA CTTTGTTA 5965

5778 CAAAGGUC A UAAUGCUU 4680 AAGCATTA GGCTAGCTACAACGA GACCTTTG 5966

5781 AGGUCAUA A UGCUUUCA 4681 TGAAAGCA GGCTAGCTACAACGA TATGACCT 5967

5783 GUCAUAAU G CUUUGAGC 4682 GCTGAAAG GGCTAGCTACAACGA ATTATGAC 5968

5790 UGCUUUCA G CAAUUGAU 4683 ATCAATTG GGCTAGCTACAACGA TGAAAGCA 5969

5793 UUUCAGCA A UUGAUGUC 4684 GACATCAA GGCTAGCTACAACGA TGCTGAAA 5970

5797 AGCAAUUG A UGUCAUUU 4685 AAATGACA GGCTAGCTACAACGA CAATTGCT 5971

5799 CAAUUGAU G UCAUUUUA 4686 TAAAATGA GGCTAGCTACAACGA ATCAATTG 5972

5802 UUGAUGUC A UUUUAUUA 4687 TAATAAAA GGCTAGCTACAACGA GACATCAA 5973

5807 GUCAUUUU A UUAAAGAA 4688 TTCTTTAA GGCTAGCTACAACGA AAAATGAC 5974

5815 AUUAAAGA A CAUUGAAA 4689 TTTCAATG GGCTAGCTACAACGA TCTTTAAT 5975

5817 UAAAGAAC A UUGAAAAA 4690 TTTTTCAA GGCTAGCTACAACGA GTTCTTTA 5976

Input Sequence = AF035121. Cut Site = R Y

Arm Length = 8. Core Sequence = GGCTAGCTACAACGA

AF035121 (Homo sapiens KDR/flk-1 protein mRNA, complete eds.; Acc# AF035121; 5830 bp)

Claims

1. A compound having Formula II: (SEQ ID NO: 5978)

5'-u_sa_sc_s a_sau ucU GAu Gag gcg aaa gcc Gaa Aag aca aB-3' wherein each a is 2'-O-methyl adenosine nucleotide, each g is a 2'-O- methyl guanosine nucleotide, each c is a 2'-O-methyl cytidine nucleotide, each u is a 2'-O-methyl uridine nucleotide, each A is adenosine, each G is guanosine, each s individually represents a phosphorothioate intemucleotide linkage, U is 2'-deoxy-2'-C-allyl uridine, and B is an inverted deoxyabasic moiety.

2. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

3. A method of administering to a cell the compound of claim 1 comprising contacting said cell with the compound under conditions suitable for said administration.

4. The method of claim 3, wherein said cell is a mammalian cell.

5. The method of claim 3, wherein said cell is a human cell.

6. The method of claim 3, wherein said administration is in the presence of a delivery reagent.

7. The method of claim 6, wherein said delivery reagent is a lipid.

8. The method of claim 7, wherein said lipid is a cationic lipid.

9. The method of claim 7, wherein said lipid is a phospholipid.

10. The method of claim 6, wherein said delivery reagent is a liposome.

11. A method of administering to a cell the compound of claim 1 in conjunction with one or more other drug comprising contacting said cell with the compound and the other drug(s) under conditions suitable for said administration.

12. A method of inhibiting ocular angiogenesis in a subject comprising the step of contacting said subject with the compound of claim 1 under conditions suitable for said inhibition.

13. The method of claim 12, wherein said angiogenesis is associated with diabetic retinopathy.

14. The method of claim 12, wherein said angiogenesis is associated with age related diabetic retinopathy.

15. A method of cleaving RNA comprising a sequence of KDR RNA comprising contacting the compound of claim 1 with said RNA under conditions suitable for the cleavage of said RNA.

16. The method of claim 15, wherein said cleavage is carried out in the presence of a divalent cation.

17. The method of claim 16, wherein said divalent cation is Mg2+.

18. A method of administering to a mammal the compound of claim 1 comprising contacting said mammal with the compound under conditions suitable for said administration.

19. The method of claim 18, wherein said mammal is a human.

20. The method of claim 18 wherein said administration is in the presence of a delivery reagent.

21. The method of claim 18, wherein said delivery reagent is a lipid.

22. The method of claim 21 , wherein said lipid is a cationic lipid.

23. The method of claim 21 , wherein said lipid is a phospholipid.

24. The method of claim 20, wherein said delivery reagent is a liposome.

25. A method for treating a subject having endometriosis, comprising contacting said subject with a nucleic acid molecule that modulates the expression of VEGF, VEGFRl, and/or VEGFR2, under conditions suitable for said treatment.

26. The method of claim 25, wherein said nucleic acid molecule is an enzymatic nucleic acid molecule.

27. The method of claim 25, wherein said nucleic acid molecule is an antisense nucleic acid molecule.

28. The method of claim 25, wherein said nucleic acid molecule is a dsRNA nucleic acid molecule.

29. The method of claim 25, wherein said nucleic acid molecule is a nucleic acid aptamer.

30. The method of claim 25, wherein said nucleic acid molecule comprises a sequence having SEQ ID NO: 5977.

31. The method of claim 26, wherein said enzymatic nucleic acid molecule has an endonuclease activity to cleave RNA encoded by an VEGFRl and/or VEGFR2 gene.

32. The method of claim 26, wherein said enzymatic nucleic acid molecule is in a hammerhead configuration.

33. The method of claim 26, wherein said enzymatic nucleic acid molecule is in an Inozyme configuration.

34. The method of claim 26, wherein said enzymatic nucleic acid molecule is in a Zinzyme configuration.

35. The method of claim 26, wherein said enzymatic nucleic acid molecule is in a DNAzyme configuration.

36. The method of claim 26, wherein said enzymatic nucleic acid molecule is in a G-cleaver configuration.

37. The method of claim 26, wherein said enzymatic nucleic acid molecule is in an Amberzyme configuration.

38. The method of claim 26, wherein said enzymatic nucleic acid molecule is an allozyme.

39. The method of claim 25, wherein said nucleic acid molecule is chemically synthesized.

40. The method of claim 25, wherein said nucleic acid molecule comprises at least one 2 '-sugar modification.

41. The method of claim 25, wherein said nucleic acid molecule comprises at least one nucleic acid base modification.

42. The method of claim 25, wherein said nucleic acid molecule comprises at least one phosphate backbone modification.

43. The method of claim 25, wherein said subject is a human.

44. A method for treating a subject having endometriosis, comprising administering to the subject a nucleic acid molecule that modulates the expression of VEGF, VEGFRl, and/or VEGFR2, under conditions suitable for said treatment.

45. The method of claim 44 wherein said administration is in the presence of a delivery reagent.

46. The method of claim 45, wherein said delivery reagent is a lipid.

47. The method of claim 46, wherein said lipid is a cationic lipid.

48. The method of claim 46, wherein said lipid is a phospholipid.

49. The method of claim 45, wherein said delivery reagent is a liposome.

50. The method of claim 44, further comprising administering one or more other drug(s).

51. The method of claim 50, wherein said other drug(s) are chosen from GnRH (gonadotropin releasing hormone) agonists, Lupron Depot (Leuprolide

Acetate), Synarel (naferalin acetate), Zolodex (goserelin acetate), Suprefact (buserelin acetate), Danazol, and oral contraceptives.

52. A compound having Formula I: (SEQ ID NO: 5977) 5' g_sa_sg_su_sugcUGAuGagg ccgaaa ggccGaaAgucugB 3'

wherein each a is 2'-O-methyl adenosine nucleotide, each g is a 2'-O- methyl guanosine nucleotide, each c is a 2'-O-methyl cytidine nucleotide, each u is a 2'-O-methyl uridine nucleotide, each A is adenosine, each G is guanosine, each s individually represents a phosphorothioate intemucleotide linkage, U is 2'-deoxy-2'-C-allyl uridine, and B is an inverted deoxyabasic moiety.

53. A composition comprising a compound of claim 52 in a pharmaceutically acceptable carrier or diluent.

54. A method of administering to a cell the compound of claim 52 comprising contacting said cell with the compound under conditions suitable for said administration.

55. The method of claim 54, wherein said cell is a mammalian cell.

56. The method of claim 54, wherein said cell is a human cell.

57. The method of claim 54, wherein said administration is in the presence of a delivery reagent.

58. The method of claim 57, wherein said delivery reagent is a lipid.

59. The method of claim 58, wherein said lipid is a cationic lipid.

60. The method of claim 58, wherein said lipid is a phospholipid.

61. The method of claim 57, wherein said delivery reagent is a liposome.

62. A method of administering to a cell the compound of claim 52 in conjunction with a chemotherapeutic agent comprising contacting said cell with the compound and the chemotherapeutic agent under conditions suitable for said administration.

63. The method of claim 62, wherein said chemotherapeutic agent is 5-fluoro uridine.

64. The method of claim 62, wherein said chemotherapeutic agent is Leucovorin.

65. The method of claim 62, wherein said chemotherapeutic agent is chosen from Mnotecan, CAMPTOSAR®, CPT-11, Camρtothecin-11, or Canipto.

66. The method of claim 62, wherein said chemotherapeutic agent is Paclitaxel.

67. The method of claim 62, wherein said chemotherapeutic agent is Carboplatin.

68. A mammalian cell comprising the compound of claim 52..

69. The mammalian cell of claim 68, wherein said mammalian cell is a human cell.

70. A method of inhibiting angiogenesis in a subject, comprising the step of contacting said subject with the compound of claim 52, under conditions suitable for said inhibition.

71. The method of claim 70, wherein said angiogenesis is tumor angiogenesis.

72. A method of treatment of a subject having a condition associated with an increased level of VEGF receptor comprising contacting cells of said subject with the compound of claim 52, under conditions suitable for said treatment.

73. The method of claim 72 further comprising the use of one or more drug therapies under conditions suitable for said treatment.

74. A method of cleaving RNA comprising a sequence of VEGFRl (flt-1), comprising contacting the compound of claim 52 with said RNA under conditions suitable for the cleavage of said RNA.

75. The method of claim 74, wherein said cleavage is carried out in the presence of a divalent cation.

76. The method of claim 75, wherein said divalent cation is Mg2+.

77. The method of claim 72, wherein said condition is cancer.

78. The method of claim 77, wherein said cancer is breast cancer.

79. The method of claim 77, wherein said cancer is lung cancer.

80. The method of claim 77, wherein said cancer is colorectal cancer.

81. The method of claim 77, wherein said cancer is renal cancer.

82. The method of claim 77, wherein said cancer is melanoma.

83. The method of claim 77, wherein said cancer is pancreatic cancer.

84. The method of claim 79, wherein said lung cancer is non-small cell lung carcinoma.

85. The method of claim 81 , wherein said renal cancer is renal cell carcinoma.

86. The method of claim 73, wherein said other therapy is 5-fluoro uridine.

87. The method of claim 73, wherein said other therapy is Leucovorin.

88. The method of claim 73, wherein said other therapy is Irinotecan, CAMPTOSAR®, CPT-11, Camptothecin-11, or Campto.

89. The method of claim 73, wherein said other therapy is Paclitaxel.

90. The method of claim 73, wherein said other therapy is Carboplatin.

91. A method of administering to a mammal the compound of claim 52 comprising contacting said mammal with the compound under conditions suitable for said administration.

92. The method of claim 91 , wherein said mammal is a human.

93. The method of claim 91 , wherein said administration is in the presence of a delivery reagent.

94. The method of claim 93, wherein said delivery reagent is a lipid.

95. The method of claim 94, wherein said lipid is a cationic lipid.

96. The method of claim 94, wherein said lipid is a phospholipid.

97. The method of claim 93, wherein said delivery reagent is a liposome.

98. A method of administering to a mammal the compound of claim 52 in conjunction with a chemotherapeutic agent comprising contacting said mammal with the compound and the chemotherapeutic agent under conditions suitable for said administration.

99. The method of claim 98, wherein said chemotherapeutic agent is 5-fluoro uridine.

100. The method of claim 98, wherein said chemotherapeutic agent is Leucovorin.

101. The method of claim 98 , wherein said chemotherapeutic agent is Irinotecan, CAMPTOSAR®, CPT-11, Camptothecin-11, or Campto.

102. The method of claim 98, wherein said chemotherapeutic agent is Paclitaxel.

103. The method of claim 98, wherein said chemotherapeutic agent is Carboplatin.