AU5661600A - Method and reagent for the treatment of diseases or conditions related to levels of vascular endothelial growth factor receptor - Google Patents

Description

S&F Ref: 416681D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

*o .01.

0. 0 0 Name and Address Sof Applicants: Actual Inventor(s): Address for Service: Ribozyme Pharmaceuticals, Incorporated 2950 Wilderness Place Boulder Colorado 80301 United States of America Chiron Corporation 4560 Horton Street Emeryville California 94608 United States of America Pamela Pavco, James McSwiggen, Dan Stinchcomb and Jaime Escobedo Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Method and Reagent for the Treatment of Diseases or Conditions Related to Levels of Vascular Endothelial Growth Factor Receptor Invention Title: The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c

SDESCRIPTION

Method and Reagent for the Treatment of Diseases or Conditions Related to Levels of Vascular Endothelial Growth Factor Receptor Background Of The Invention 5 This invention relates to methods and reagents for O.O• the treatment of diseases or conditions relating to the levels of expression of vascular endothelial growth factor (VEGF) receptor(s).

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 15 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, 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-linked 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 12"I-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 Scells, receptors of 150 and the 130 kDa have been identi- Sfied. The VEGF receptors belong to the superfamily of receptor tyrosine kinases (RTKs) characterized by a conserved cytoplasmic catalytic kinase domain and a hydrophylic kinase sequence. The extracellular domains of the VEGF receptors consist of seven immunoglobulin-like domains that are thought to be involved in VEGF binding 20 functions.

The two most abundant and high-affinity receptors of VEGF are flt-1 (fms-like tyrosine kinase) cloned by Shibuya et al., 1990 Oncogene 5, 519 and KDR (kinaseinsert-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). Recently it has been shown that 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. Following is a brief summary of evidence supporting the involvement of VEGF in various diseases: S1) Tumor angiogenesis: Increased levels of VEGF gene expression have been reported in vascularized and edemaassociated brain tumors (Berkman et al., 1993 J. Clini.

Invest. 91, 153). A more direct demostration 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).

2) Ocular diseses: Aiello et al., 1994 New Engl. J.

Med. 331, 1480, showed that the ocular fluid, of a major- 15 ity of patients suffering from diabetic retinopathy and other retinal disorders, contains a high concentration of VEGF. Miller et al., 1994 Am. J. Pathol. 145, 574, reported elevated levels of VEGF mRNA in patients suffering from retinal ischemia. These observations support a 20 direct role for VEGF in ocular diseases.

3) Psoriasis: Detmar et al., 1994 J. Exp. Med. 180, 1141 reported that VEGF and its receptors were overexpressed 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.

In addition to the above data on pathological conditions involving excessive angiogenesis, 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 flk-1 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.

15 Invest. 91, 2235). Furthermore, transgenic mice lacking either of the VEGF receptors are defective in blood vessel formation, infact these mouse do not survive; flk-1 appears to be required for differentiation of endothelial cells, while flt-1 appears to be required at later stages 20 of vessel formation (Shalaby et al., 1995 Nature 376, 62; Fung et al., 1995 Nature 376, 66). Thus, these receptors must be present to properly signal endothelial cells or their precursors to respond to vascularization-promoting stimuli.

All of the conditions listed above, involve extensive vascularization. This hyper-stimulation of endothelial cells may be alleviated by VEGF antagonists. Thus most of the therapeutic efforts for the above conditions have concentrated on finding inhibitors of the VEGF protein.

Kim et al., 1993 Nature 362, 841 have been successful in inhibiting VEGF-induced tumor growth and angiogenesis in nude mice by treating the mice with VEGF-specific monoclonal antibody.

Koch et al., 1994 J. Immunol. .152, 4149 showed that the mitogenic activity of microvascular endothelial cells found in rheumatoid arthritis (RA) synovial tissue explants and the chemotactic property of endothelial cells from RA synovial fluid can be neutralized significantly by treatment with VEGF-specific antibodies.

Ullrich et al., International PCT Publication No. WO 94/11499 and Millauer et al., 1994 Nature 367, 576 used a soluble form of flk-1 receptor (dominant-negative mutant) to prevent VEGF-mediated tumor angiogenesis in immuno-deficient mice.

Kendall and Thomas, International PCT Publication No. WO 94/21679 describe the use of naturally occuring or recombinantly-engineered soluble forms of VEGF receptors to inhibit VEGF activity.

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

Jellinek et al., 1994 Biochemistry 33, 10450 describe the use of 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 anti-VEGF receptor monoclonal antibodies to neutralize the effect of VEGF on 15 endothelial cells.

Summary of the Invention The invention features novel nucleic acid-based techniques enzymatic nucleic acid molecules (ribozymes), antisense nucleic acids, 2-5A antisense chimeras, triplex DNA, antisense nucleic acids containing RNA cleaving chemical groups (Cook et al., U.S. Patent 5,359,051)] and methods for their use to down regulate or inhibit the expression of receptors of VEGF (VEGF-R).

In a preferred embodiment, the invention features use of one or more of the nucleic acid-based techniques to inhibit the expression of fit-1 and/or flk-1/KDR receptors.

By "inhibit" it is meant that the activity of VEGF-R or level of mRNAs or equivalent RNAs encoding VEGF-R is reduced below that observed in the absence of the nucleic acid. In one embodiment, inhibition with ribozymes [R:\LIIBA02409.doc:aak V preferably is below that level observed in the presence of an enzymatically inactive RNA molecule that is able to bind to the same site on the mRNA, but is unable to cleave that RNA. In another embodiment, inhibition with antisense oligonucleotides is preferably below that level observed in the presence of for example, an oligonucleotide with scrambled sequence or with mismatches.

By "enzymatic nucleic acid molecule" it is meant an RNA 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 target RNA. That is, the enzymatic RNA molecule is able to intermolecularly cleave RNA and thereby inactivate a target RNA molecule. This complementary regions allow 15 sufficient hybridization of the enzymatic RNA molecule to the target RNA and thus permit cleavage. One hundred percent complementarity is preferred, but complementarity as low as 50-75% may also be useful in this invention. By "equivalent" RNA to VEGF-R is meant to include those S 20 naturally occurring RNA molecules in various animals, including human, mice, rats, rabbits, primates and pigs.

By "antisense nucleic acid" it is meant a nonenzymatic nucleic acid molecule that binds to target RNA by means of RNA-RNA or RNA-DNA or RNA-PNA (protein nucleic acid; Egholm et al., 1993 Nature 365, 566) interactions and alters the activity of the target RNA (for a review see Stein and Cheng, 1993 Science 261, 1004).

By "2-5A antisense chimera" it is meant, an antisense oligonucleotide containing a 5' phosphorylated linked adenylate residues. These chimeras bind to target RNA in a sequence-specific manner and activate a cellular ribonuclease which, in turn, cleaves the target RNA (Torrence et al., 1993 Proc. Natl. Acad. Sci.

USA 90, 1300).

By "triplex DNA" it is meant an oligonucleotide that can bind to a double-stranded DNA in a sequence-specific manner to form a triple-strand helix. Formation of such 7 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).

By "gene" it is meant a nucleic acid that encodes an

RNA.

By "complementarity" it is meant a nucleic acid that can form hydrogen bond(s) with other RNA sequence by either traditional Watson-Crick or other non-traditional types (for example, Hoogsteen type) of base-paired interactions.

Six basic varieties of naturally-occurring enzymatic RNAs are known presently. Each can catalyze the hydrolysis of RNA phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological condi- 15 tions. Table I summarizes some of the characteristics of these ribozymes. In general, enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding portion of a enzymatic nucleic acid which is held in close proximity to an enzymatic 20 portion of the molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds a target RNA through complementary basepairing, and once bound to the correct site, acts enzymatically to cut the target RNA. Strategic cleavage of such a target RNA will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its RNA target, it is released from that RNA 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 RNA. In 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 RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can completely eliminate catalytic activity of a ribozyme.

Ribozymes that cleave the specified sites in VEGF-R mRNAs represent a novel therapeutic approach to treat tumor angiogenesis, ocular diseases, rhuematoid arthritis, psoriasis and others. Applicant indicates that ribozymes are able to inhibit the activity of VEGF-R (specifically flt-1 and flk-1/KDR) and that the catalytic activity of the ribozymes is required for their inhibitory effect.

Those of ordinary skill in the art will find that it is clear from the examples described that other ribozymes that cleave VEGF-R mRNAs may be readily designed and are within the invention.

In preferred embodiments of this invention, the enzymatic nucleic acid molecule is formed in a hammerhead or hairpin motif, but may also be formed in the motif of 15 a hepatitis delta virus, group I intron or RNaseP RNA (in association with an RNA guide sequence) or Neurospora

VS

RNA. Examples of such hammerhead motifs are described by 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, and Hampel et al., 1990 Nucleic Acids Res. 18, 299, and an example of the hepatitis delta virus motif is described by Perrotta and Been, 1992 Biochemistry 31, 16; of the RNaseP motif by Guerrier-Takada et al., 1983 Cell 35, 849, Neurospora

VS

RNA ribozyme motif is 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) and of the Group I intron by Cech et al., U.S. Patent 4,987,071. These specific motifs 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 gene RNA regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart an RNA cleaving activity to the molecule.

In a preferred embodiment the invention provides a method for producing a class of enzymatic cleaving agents which exhibit a high degree of specificity for the RNA of a desired target. The enzymatic nucleic acid molecule is preferably targeted to a highly conserved sequence region of target mRNAs encoding VEGF-R proteins (specifically flt-1 and flk-1/KDR) such that specific treatment of a disease or condition can be provided with either one or several enzymatic nucleic acids. Such enzymatic nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required. Alternatively, the ribozymes can be expressed from DNA and/or RNA vectors that are delivered to specific cells.

Synthesis of nucleic acids greater than 100 nucleo- 15 tides in length is difficult using automated methods, and the therapeutic cost of such molecules is prohibitive. In this invention, small nucleic acid motifs antisense oligonucleotides, hammerhead or the hairpin ribozymes) are used for exogenous delivery. The simple structure of 20 these molecules increases the ability of the nucleic acid to invade targeted regions of the mRNA structure.

However, these nucleic acid molecules can also be expressed within cells from eukaryotic promoters Izant and Weintraub, 1985 Science 229, 345; McGarry and Lindquist, 1986 Proc. Natl. Acad. Sci. USA 83, 399; Sullenger-Scanlon et al., 1991, Proc. Natl. 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). 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 ribozyme (Draper et al., PCT WO93/23569, and Sullivan et al., PCT W094/02595, both hereby incorporated in their totality by reference herein; Ohkawa et al., 1992 Nucleic Acids SymD.

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).

Such nucleic acids are useful for the prevention of the diseases and conditions discussed above, and any other diseases or conditions that are related to the levels of VEGF-R (specifically flt-i and flk-1/KDR) in a cell or tissue.

By "related" is meant that the reduction of VEGF-R (specifically flt-1 and flk-1/KDR) RNA levels and thus reduction in the level of the respective protein will 15 relieve, to some extent, the symptoms of the disease or condition.

S. Ribozymes are added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues. The nucleic 20 acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through injection, infusion pump or stent, with or without their incorporation in biopolymers. In preferred embodiments, the ribozymes have binding arms which are complementary to the sequences in Tables II to IX. Examples of such ribozymes also are shown in Tables II to IX. Examples of such ribozymes consist essentially of sequences defined in these Tables. By "consists essentially of" is meant that the active ribozyme contains an enzymatic center equivalent to those in the examples, and binding arms able to bind mRNA such that cleavage at the target site occurs. Other sequences may be present which do not interfere with such cleavage.

In another aspect of the invention, ribozymes that cleave target RNA molecules and inhibit VEGF-R (specifically flt-1 and flk-1/KDR) activity are expressed from transcription units inserted into DNA or RNA vectors. The Srecombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors could be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the ribozymes are delivered as described above, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of ribozymes. Such vectors might be repeatedly administered as necessary.

Once expressed, the ribozymes cleave the target mRNA.

Delivery of ribozyme expressing vectors could 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 15 other means that would allow for introduction into the desired target cell.

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

Other features and advantages of the invention will 20 be apparent from the following description of the preferred embodiments thereof, and from the claims.

Description Of The Preferred Embodiments First the drawings will be described briefly.

Drawings Figure 1 is a diagrammatic representation of the hammerhead ribozyme domain known in the art. Stem II can be a 2 base-pair long.

Figure 2a is a diagrammatic representation of the hammerhead ribozyme domain known in the art; Figure 2b is a diagrammatic representation of the hammerhead ribozyme as divided by Uhlenbeck (1987, Nature, 327, 596-600) into a substrate and enzyme portion; Figure 2c is a similar diagram showing the hammerhead divided by Haseloff and Gerlach (1988, Nature, 334, 585-591) into two portions; and Figure 2d is a similar diagram showing the hammerhead divided by Jeffries and Symons (1989, Nucl. Acids. Res., 17, 1371-1371) into two portions.

Figure 3 is a diagramatic representation of the general structure of a hairpin ribozyme. Helix 2 (H2) is provided with a least 4 base pairs n is 1, 2, 3 or 4) and helix 5 can be optionally provided of length 2 or more bases (preferably 3 20 bases, m is from 1 or more). Helix 2 and helix 5 may be covalently linked by one or more bases r is a 1 base). Helix 1, 4 or 5 may also be extended by 2 or more base pairs 4 base pairs) to stabilize the ribozyme structure, and preferably is a protein binding site. In each instance, each N and N' independently is any normal or modified base eeoc and each dash represents a potential base-pairing inter- 15 action. These nucleotides may be modified at the sugar, base or phosphate. Complete base-pairing is not required in the helices, but is preferred. Helix 1 and 4 can be of any size o and p is each independently from 0 to any number, 20) as long as some base-pairing is 20 maintained. Essential bases are shown as specific bases in the structure, but those in the art will recognize that one or more may be modified chemically (abasic, base, sugar and/or phosphate modifications) or replaced with i another base without significant effect. Helix 4 can be formed from two separate molecules, without a connecting loop. The connecting loop when present may be a ribonucleotide with or without modifications to its base, sugar or phosphate. is a 2 bases. The connecting loop can also be replaced with a non-nucleotide linker molecule. H refers to bases A, U, or C. Y refers to pyrimidine bases. refers to a covalent bond.

Figure 4 is a representation of the general structure of the hepatitis delta virus ribozyme domain known in the art.

Figure 5 is a representation of the general structure of the VS RNA ribozyme domain.

Figure 6 is a schematic representation of an RNAseH accessibility assay. Specifically, the left side of Figure 6 is a diagram of complementary DNA oligonucleotides bound to accessible sites on the target RNA.

Complementary DNA oligonucleotides are represented by broad lines labeled A, B, and C. Target RNA is represented by the thin, twisted line. The right side of Figure 6 is a schematic of a gel separation of uncut target RNA from a cleaved target RNA. Detection of target RNA is by autoradiography of body-labeled, T7 transcript.

The bands common to each lane represent uncleaved target RNA; the bands unique to each lane represent the cleaved products.

Figure 7 shows the effect of hammerhead ribozymes 15 targeted against flt-1 receptor on the binding of VEGF to the surface of human microvascular endothelial cells.

Sequences of the ribozymes used are shown in Table II; the length of stem II region is 3 bp. The hammerhead ribozymes were chemically modified such that the ribozyme 20 consists of ribose residues at five positions (see Figure 11); U4 and U7 positions contain 2'-NH 2 modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions; four nucleotides at the 5' terminus contains phosphorothioate substitutions. Additionally, the 3' end of the ribozyme contains a linked inverted abasic deoxyribose. The results of two separate experiments are shown as separate bars for each set. Each bar represents the average of triplicate samples. The standard deviation is shown with error bars. For the flt-1 data, 500 nM ribozyme (3:1 charge ratio with LipofectAMINE®) was used.

Control 1-10 is the control for ribozymes 307-2797, control 11-20 is the control for ribozymes 3008-5585. The Control 1-10 and Control 11-20 represent the treatment of cells with LipofectAMINE® alone without any ribozymes.

Figure 8 shows the effect of hammerhead ribozymes targeted against KDR receptor on the binding of VEGF to KDR on the surface of human microvascular endothelial Scells. Sequences of the ribozymes used are shown in Table IV; the length of stem II region is 3 bp. The hammerhead ribozymes were chemically modified such that the ribozyme consists of ribose residues at five positions (see Figure 11); U4 and U7 positions contain 2'-NH 2 modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions; four nucleotides at the 5' terminus contains phosphorothioate substitutions. Additionally, the 3' end of the ribozyme contains a linked inverted abasic deoxyribose. The Control 1-10 and Control 11-20 represent the treatment of cells with LipofectAMINE® alone without any ribozymes. Irrel. RZ, is a control experiment wherein the cells are treated with a non-KDR-targeted ribozyme complexed with Lipofectamine®. 200 nM ribozyme (3:1 15 charge ratio with LipofectAMINE®) was used. In addition to the KDR-targeted ribozymes, the effect on VEGF binding of a ribozyme targeted to an irrelevant mRNA (irrel. RZ) is also shown. Because the affinity of KDR for VEGF is about 10-fold lower than the affinity of flt-1 for VEGF, 20 a higher concentration of VEGF was used in the binding assay.

Figure 9 shows the specificity of hammerhead ribozymes targeted against flt-1 receptor. Inhibition of the binding of VEGF, urokinase plasminogen activator (UPA) and fibroblast growth factor (FGF) to their corresponding receptors as a function of anti-FLT ribozymes is shown.

The sequence and description of the ribozymes used are as described under Figure 7 above. The average of triplicate samples is given; percent inhibition as calculated below.

Figure 10 shows the inhibition of the proliferation of Human aortic endothelial cells (HAEC) mediated by phosphorothioate antisense oligodeoxynucleotides targeted against human KDR receptor RNA. Cell proliferation (O.D.

490) as a function of antisense oligodeoxynucleotide concentration is shown. KDR 21AS represents a 21 nt phosphorothioate antisense oligodeoxynucleotide targeted against KDR RNA. KDR 21 Scram represents a 21 nt U phosphorothioate oligodeoxynucleotide having a scrambled sequence. LF represents the lipid carrier Lipofectin.

Figure 11 shows in vitro cleavage of flt-1 RNA by hammerhead ribozymes. A) diagrammatic representation of hammerhead ribozymes targeted against flt-1 RNA. The hammerhead (HH) ribozymes were chemically modified such that the ribozyme consists of ribose residues at five positions; U4 and U7 positions contain 2'-NH, modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions; four nucleotides at the terminus contains phosphorothioate substitutions.

Additionally, the 3' end of the ribozyme contains a 3'-3' linked inverted abasic deoxyribose (designated as 3'-iH).

1358 HH-A and 4229 HH-A contain 3 base-paired stem II 15 region. 1358 HH-B and 4229 HH-B contain 4 base-paired stem II region. B) and C) shows in vitro cleavage kinetics of HH ribozymes targeted against sites 1358 and 4229 within the flt-1 RNA.

Figure 12 shows inhibition of human microvascular 20 endothelial cell proliferation mediated by anti-flt-i hammerhead ribozymes. A) Diagrammatic representation of hammerhead (HH) ribozymes targeted against sites 1358 and 4229 within the the flt-i RNA. B) Graphical representation of the inhibition of cell proliferation mediated by 1358HH and 4229HH ribozymes.

Figure 13 shows inhibition of human microvascular endothelial cell proliferation mediated by anti-KDR hammerhead ribozymes. The figure is a graphical representation of the inhibition of cell proliferation mediated by hammerhead ribozymes targeted against sites 527, 730, 3702 and 3950 within the KDR RNA. Irrelevant HH RZ is a hammerhead ribozyme targeted to an irrelevant target. All of these ribozymes, including the Irrelevant HH RZ, were chemically modified such that the ribozyme consists of ribose residues at five positions; U4 and U7 positions contain 2'-NH 2 modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions; four U nucleotides at the 5' termini contain phosphorothioate substitutions. Additionally, the 3' end of the ribozyme contains a linked inverted abasic deoxyribose Figure 14 shows in vitro cleavage of KDR RNA by hammerhead ribozymes. The hammerhead (HH) ribozymes were chemically modified such that the ribozyme consists of ribose residues at five positions; U4 and U7 positions contain 2'-NH 2 modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions. Additionally, the 3' end of the ribozyme contains a linked inverted abasic deoxyribose (designated as 726 HH and 527 HH contain 4 base-paired stem II region. Percent in vitro cleavage kinetics as a function of time of HH 15 ribozymes targeted against sites 527 and 726 within the KDR RNA is shown.

Figure 15 shows in vitro cleavage of KDR RNA by hammerhead ribozymes. The hammerhead (HH) ribozymes were chemically modified such that the ribozyme consists of S 20 ribose residues at five positions; U4 and U7 positions contain 2'-NH 2 modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions. Additionally, the 3' end of the ribozyme contains a linked inverted abasic deoxyribose (designated as 3702 HH and 3950 HH contain 4 base-paired stem II region.

Percentin vitro cleavage kinetics as a function of time of HH ribozymes targeted against sites 3702 and 3950 within the KDR RNA is shown.

Figure 16 shows in vitro cleavage of RNA by hammerhead ribozymes that are targeted to sites that are conserved between flt-i and KDR RNA. The hammerhead (HH) ribozymes were chemically modified such that the ribozyme consists of ribose residues at five positions; U4 and U7 positions contain 2'-NH 2 modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions.

Additionally, the 3' end of the ribozyme contains a 3'-3' linked inverted abasic deoxyribose (designated as 3'-iH).

FLT/KDR-I HH ribozyme was synthesized with either a 4 base-paired or a 3 base-paired stem II region. FLT/KDR-I HH can cleave site 3388 within flt-1 RNA and site 3151 within KDR RNA. Percent in vitro cleavage kinetics as a function of time of HH ribozymes targeted against sites 3702 and 3950 within the KDR RNA is shown.

Figure 17 shows inhibition of human microvascular endothelial cell proliferation mediated by anti-KDR and anti-flt-1 hammerhead ribozymes. The figure is a graphical representation of the inhibition of cell proliferation mediated by hammerhead ribozymes targeted against sites KDR sites-527, 726 or 3950 or flt-i site 4229. The figure also shows enhanced inhibition of cell proliferation by a combination of flt-i and KDR hammerhead ribo- 15 zymes. 4229+527, indicates the treatment of cells with both the fit 4229 and the KDR 527 ribozymes. 4229+726, indicates the treatment of cells with both the fit 4229 and the KDR 726 ribozymes. 4229+3950, indicates the treatment of cells with both the fit 4229 and the KDR 3950 20 ribozymes. VEGF indicates the basal level of cell proliferation in the absence of VEGF. A, indicates catalytically active ribozyme; I, indicates catalytically inactive ribozyme. All of these ribozymes were chemically modified such that the ribozyme consists of ribose residues at five positions; U4 and U7 positions contain 2'-NH 2 modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions; four nucleotides at the termini contain phosphorothioate substitutions.

Additionally, the 3' end of the ribozyme contains a 3'-3' linked inverted abasic deoxyribose Figure 18 shows the inhibition of VEGF-induced angiogenesis in rat cornea mediated by anti-flt-1 hammerhead ribozyme. All of these ribozymes were chemically modified such that the ribozyme consists of ribose residues at five positions; U4 position contains 2'-C-allyl modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions; four nucleotides at the 5' termini contain phosphorothioate substitutions. Additionally, the 3' end of the ribozyme contains a linked inverted abasic deoxyribose A decrease in the Surface Area corresponds to a reduction in angiogenesis. VEGF alone, corresponds to treatment of the cornea with VEGF and no ribozymes. Vehicle alone, corresponds to the treatment of the cornea with the carrier alone and no VEGF. This control gives a basal level of Surface Area. Active 4229 HH, corresponds to the treatment of cornea with the flt-1 4229 HH ribozyme in the absence of any VEGF. This control also gives a basal level of Surface Area. Active 4229 HH VEGF, corresponds to the co-treatment of cornea with the flt-1 4229 HH ribozyme and VEGF. Inactive 4229 HH VEGF, corresponds to the co-treatment of cornea with a cata- 15 lytically inactive version of 4229 HH ribozyme and VEGF.

Ribozvmes Ribozymes of this invention block to some extent VEGF-R (specifically flt-i and flk-1/KDR) production and can be used to treat disease or diagnose such disease.

Ribozymes will be delivered to cells in culture, to cells or tissues in animal models of angiogenesis and/or RA and to human cells or tissues ex vivo or in vivo. Ribozyme cleavage of VEGF-R RNAs (specifically RNAs that encode flt-1 and flk-1/KDR) in these systems may alleviate disease symptoms.

Target sites Targets for useful ribozymes can be determined as disclosed in Draper et al., International PCT Publication No. WO 95/13380, 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 W limiting to those in the art. Ribozymes to such targets are designed as described in those applications and synthesized to be tested in vitro and in vivo, as also described.

The sequence of human and mouse flt-1, KDR and/or flk-1 mRNAs were screened for optimal ribozyme target sites using a computer folding algorithm. Hammerhead or hairpin ribozyme cleavage sites were identified. These sites are shown in Tables II to IX (all sequences are to 3' in the tables; X can be any base-paired sequence, the actual sequence is not relevant here). The nucleotide base position is noted in the Tables as that site to be cleaved by the designated type of ribozyme. While mouse and human sequences can be screened and ribozymes there- 15 after designed, the human targeted sequences are of most utility. However, as discussed in Stinchcomb et al., "Method and Composition for Treatment of Restenosis and Cancer Using Ribozymes," filed May 18, 1994, U.S.S.N.

08/245,466, mouse targeted ribozymes may be useful to test 20 efficacy of action of the ribozyme prior to testing in humans. The nucleotide base position is noted in the Tables as that site to be cleaved by the designated type of ribozyme.

Hammerhead or hairpin ribozymes were designed that could bind and cleave target RNA in a sequence-specific manner. The ribozymes were individually analyzed by computer folding (Jaeger et al., 1989 Proc. Natl. Acad.

Sci. USA, 86, 7706) to assess whether the ribozyme sequences fold into the appropriate secondary structure.

Those ribozymes with unfavorable intramolecular interactions between the binding arms and the catalytic core were eliminated from consideration. Varying binding arm lengths can be chosen to optimize activity.

Referring to Figure 6, mRNA is screened for accessible cleavage sites by the method described generally in Draper et al., PCT W093/23569, hereby incorporated by reference herein. Briefly, DNA oligonucleotides W complementary to potential hammerhead or hairpin ribozyme cleavage sites were synthesized. A polymerase chain reaction is used to generate substrates for T7 RNA polymerase transcription from human and mouse flt-1, KDR and/or flk-1 cDNA clones. Labeled RNA transcripts are synthesized in vitro from the templates. The oligonucleotides and the labeled transcripts were annealed, RNAseH was added and the mixtures were incubated for the designated times at 37'C. Reactions are stopped and RNA separated on sequencing polyacrylamide gels. The percentage of the substrate cleaved is determined by autoradiographic quantitation using a PhosphorImaging system. From these data, hammerhead or hairpin ribozyme sites are chosen as the most accessible.

15 Ribozymes of the hammerhead or hairpin motif were designed to anneal to various sites in the mRNA message.

The binding arms are complementary to the target site sequences described above. The ribozymes were chemically synthesized. The method of. synthesis used follows the 20 procedure for normal RNA synthesis 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 and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. Small scale synthesis were conducted on a 394 Applied Biosystems, Inc. synthesizer using a modified 2.5 imol scale protocol with a 5 min coupling step for alkylsilyl protected nucleotides and min coupling step for 2 '-O-methylated nucleotides. Table XI outlines the amounts, and the contact times, of the reagents used in the synthesis cycle. A 6.5-fold excess (163 AL of 0.1 M 16.3 Amol) of phosphoramidite and a 24-fold excess of S-ethyl tetrazole (238 AL of 0.25 M 59.5 ymol) relative to polymer-bound 5'-hydroxyl was used in each coupling cycle. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by 21 colorimetric quantitation of the trityl fractions, were 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer: detritylation solution was 2% TCA in methylene chloride (ABI); capping was performed with 16% N-methyl imidazole in THF (ABI) and acetic anhydride/10% 2 ,6-lutidine in THF (ABI); oxidation solution was 16.9 mM I2, 49 mM pyridine, 9% water in THF (Millipore). B J Synthesis Grade acetonitrile was used directly from the reagent bottle. S-Ethyl tetrazole solution (0.25 M in acetonitrile) was made up from the solid obtained from American International Chemical, Inc.

Deprotection of the RNA was performed as follows. The polymer-bound oligoribonucleotide, trityl-off, was trans- 15 ferred from the synthesis column to a 4mL glass screw top vial and suspended in a solution of methylamine (MA) at C for 10 min. After cooling to -20 the supernatant was removed from the polymer support. The support was washed three times with 1.0 mL of EtOH:MeCN:H 2 0/3:1:1, 20 vortexed and the supernatant was then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, were dried to a white powder.

The base-deprotected oligoribonucleotide was resuspended in anhydrous TEAOHF/NMP solution (250 AL of a solution of 1.5mL N-methylpyrrolidinone, 750 AL TEA and mL TEA3HF to provide a 1.4M HF concentration) and heated to 65'C for 1.5 h. The resulting, fully deprotected, oligomer was quenched with 50 mM TEAB (9 mL) prior to anion exchange desalting.

For anion exchange desalting of the deprotected oligomer, the TEAB solution was loaded onto a Qiagen 500® anion exchange cartridge (Qiagen Inc.) that was prewashed with 50 mM TEAB (10 mL). After washing the loaded cartridge with 50 mM TEAB (10 mL), the RNA was eluted with 2 M TEAB (10 mL) and dried down to a white powder.

Inactive hammerhead ribozymes were synthesized by substituting a U for G s and a U for (numbering from W Hertel, K. et al., 1992, Nucleic Acids Res., 3252).

The average stepwise coupling yields were >98% (Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684).

Hairpin ribozymes are synthesized in two parts and annealed to reconstruct the active ribozyme (Chowrira and Burke, 1992 Nucleic Acids Res., 20, 2835-2840). Ribozymes are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51).

All ribozymes are modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'-flouro, 2'-O-methyl, 2'-H (for a review see Usman and Cedergren, 1992 TIBS 17, 15 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 Usman et al., PCT Publication No. W095/23225, the totality of which is hereby incor- 20 porated herein by reference) and are resuspended in water.

The sequences of the ribozymes that are chemically synthesized, useful in this study, are shown in Tables II to IX. Those in the art will recognize that these sequences are representative only of many more such sequences where the enzymatic portion of the ribozyme (all but the binding arms) is altered to affect activity.

Stem-loop IV sequence of hairpin ribozymes listed in for example Table III (5'-CACGUUGUG-3') can be altered (substitution, deletion, and/or insertion) to contain any sequence, provided a minimum of two base-paired stem structure can form. The sequences listed in Tables II to IX may be formed of ribonucleotides or other nucleotides or non-nucleotides. Such ribozymes are equivalent to the ribozymes described specifically in the Tables.

SOptimizing Ribozyme Activity Ribozyme activity can be optimized as described by Stinchcomb et al., supra. The details will not be repeated here, but include altering the length of the ribozyme binding arms (stems I and III, see Figure 2c), or chemically synthesizing ribozymes with modifications that prevent their degradation by serum ribonucleases (see 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., International Publication No. WO 93/15187; Rossi et al., International Publication No. WO 91/03162; Beigelman et al., 1995 J. Biol Chem. in press; as well as Sproat, US 15 Patent No. 5,334,711 which describe various chemical modifications that can be made to the sugar moieties of enzymatic RNA molecules) Modifications which enhance their efficacy in cells, and removal of stem II bases to shorten RNA synthesis times and reduce chemical require- 20 ments are desired. (All these publications are hereby •incorporated by reference herein).

Sullivan, et al., supra, describes the general methods for delivery of enzymatic RNA molecules.

Ribozymes may 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. For some indications, ribozymes may be directly delivered ex vivo to cells or tissues with or without the aforementioned vehicles. Alternatively, the RNA/vehicle combination is locally delivered by direct injection or by use of a catheter, infusion pump or stent.

Other routes of delivery include, but are not limited to, intravascular, intramuscular, subcutaneous or joint injection, aerosol inhalation, oral (tablet or pill form), topical, systemic, ocular, intraperitoneal and/or intra- W thecal delivery. More detailed descriptions of ribozyme delivery and administration are provided in Sullivan et al., supra and Draper et al., supra which have been incorporated by reference herein.

Another means of accumulating high concentrations of a ribozyme(s) within cells is to incorporate the ribozymeencoding sequences into a DNA or RNA expression vector.

Transcription of the ribozyme sequences are driven from a promoter for eukaryotic RNA polymerase I (pol

RNA

polymerase II (pol II), or RNA polymerase III (pol III).

Transcripts from pol II or pol III promoters will be expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type will depend on the nature of the gene regulatory sequences (enhancers, 15 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.

U S A, 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; Thompson et al., 1995 supra). Several investigators have demonstrated that ribozymes expressed from such promoters can function in mammalian cells 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. U S A, 90, 6340-4; L'Huillier et al., 1992 EMBO J. 11, 4411-8; Lisziewicz et al., 1993 Proc. Natl. Acad. Sci. U. S. 90, 8000-4; Thompson et al., 1995 Nucleic Acids Res. 23, 2259). 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).

M In a preferred embodiment of the invention, a transcription unit expressing a ribozyme that cleaves RNAs that encode flt-1, KDR and/or flk-i are inserted into a plasmid DNA vector or an adenovirus or adeno-associated virus DNA viral vector or a retroviral RNA vector. Viral vectors have been used to transfer genes and lead to either transient or long term gene expression (Zabner et al., 1993 Cell 75, 207; Carter, 1992 Curr. Opi. Biotech.

3, 533). The adenovirus, AAV or retroviral vector is delivered as recombinant viral particles. The DNA may be delivered alone or complexed with vehicles (as described for RNA above) The recombinant adenovirus or AAV or eec- retroviral particles are locally administered to the site of treatment, through incubation or inhalation in 15 vivo or by direct application to cells or tissues ex vivo. Retroviral vectors have also been used to express oo ribozymes in mammalian cells (Ojwang et al., 1992 supra; ooo Thompson et al., 1995 supra).

flt-1, KDR and/or flk-1 are attractive nucleic o. 20 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 eoe animal models. Finally, the disease conditions are Sserious and current therapies are inadequate. Whereas protein-based therapies would inhibit VEGF activity nucleic acid-based therapy provides a direct and elegant approach to directly modulate flt-1, KDR and/or flk-1 expression.

Because flt-i and KDR mRNAs are highly homologous in certain regions, some ribozyme target sites are also homologous (see Table X) In this case, a single ribozyme will target both flt-i and KDR mRNAs. At partially homologous sites, a single ribozyme can sometimes be designed to accomodate a site on both mRNAs by including G/U basepairing. For example, if there is a G present in a ribozyme target site in KDR mRNA at the same position there is an A in the flt-i ribozyme target site, the W ribozyme can be synthesized with a U at the complementary position and it will bind both to sites. The advantage of one ribozyme that targets both VEGF-R mRNAs is clear, especially in cases where both VEGF receptors may contribute to the progression of angiogenesis in the disease state.

"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 *oooo 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.

15 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).

20 "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. In ooo "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).

Example 1: flt-1, KDR and/or flk-1 ribozymes By engineering ribozyme motifs applicant has designed several ribozymes directed against flt-1, KDR and/or flk-1 encoded mRNA sequences. These ribozymes were synthesized with modifications that improve their nuclease resistance (Beigelman et al., 1995 J Biol. Chem. 270, 25702) and enhance their activity in cells. The ability of ribozymes to cleave target sequences in vitro was evaluated essentially as described in Thompson et al., PCT Publication No. WO 93/23057; Draper et al., PCT Publication No. WO 95/04818.

Example 2: Effect of ribozymes on the binding of VEGF to flt-1, KDR and/or flk-1 receptors Several common human cell lines are available that express endogenous flt-1, KDR and/or flk-1. flt-1,

KDR

and/or flk-1 can be detected easily with monoclonal antibodies. Use of appropriate fluorescent reagents and fluorescence-activated cell-sorting (FACS) will permit 10 direct quantitation of surface flt-1, KDR and/or flk-1 on a cell-by-cell basis. Active ribozymes are expected to directly reduce flt-1, KDR and/or flk-1 expression and :.thereby reduce VEGF binding to the cells. In this example, human umbelical cord microvascular endothelial cells were used.

Cell Preparation: Plates are coated with 1.5% gelatin and allowed to stand for one hour. Cells microvascular endothelial cells derived from human umbilical cord vein) are plated at 20,000 cells/well (24 well plate) in 200 ml growth media and incubated overnight 1 doubling) to yield -40,000 cells (75-80% confluent).

Ribozyme treatment: Media is removed from cells and the cells are washed two times with 300 ml IX PBS: Ca 2 Mg 2 mixture. A complex of 200-500 nM ribozyme and LipofectAMINE® (3:1 lipid: phosphate ratio) in 200 ml OptiMEM® FBS) was added to the cells. The cells are incubated for 6 hr (equivalent to 2-3 VEGF-R turnovers).

125 VEGF binding assay: The assay is carried out on ice to inhibit internalization of VEGF during the experiment. The media containing the ribozyme is removed from the cells and the cells 28 O are washed twice with with 300 ml IX PBS: Ca 2 Mg" 2 mixture containing 1% BSA. Appropriate 1251 VEGF solution (100,000 cpm/well, 10 X cold IX PBS, 1% BSA) was applied to the cells. The cells are incubated on ice for 1 h. 1251 VEGF-containing solution is removed and the cells are washed three times with with 300 ml lX PBS: Ca 2 Mg 2 mixture containing 1% BSA. To each well 300 ml of 100 mM Tris-HCl, pH 8.0, 0.5% Triton X-100 was added and the the mixture was incubated for 2 min. The 125I VEGF-binding was quantitated using standard scintillation counting techniques. Percent inhibition was calculated as follows: Percent Inhibition cpm 125I VEGF bound by the ribozyme-treated samples x 100 cpm 12 VEGF bound by the Control sample Example 3: Effect of hammerhead ribozymes targeted against flt-i receptor on the binding of VEGF Hammerhead ribozymes targeted to twenty sites within flt-l RNA were synthesized as described above. Sequence of the ribozymes used are shown in Table II; the length of 20 stem II region is 3 bp. The hammerhead ribozymes were chemically modified such that the ribozyme consists of ':*ribose residues at five positions; U4 and U7 positions contain 2'-NH 2 modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions; four nucleotides at the 5' terminus contains phosphorothioate substitutions. Additionally, 3' end of the ribozyme contains a linked inverted abasic ribose.

Referring to Figure 7, the effect of hammerhead ribozymes targeted against flt-1 receptor on the binding of VEGF to flt-i on the surface of human microvascular endothelial cells is shown. The majority of the ribozymes tested were able to inhibit the expression of flt-i and thereby were able to inhibit the binding of VEGF.

In order to determine the specificity of ribozymes targeted against flt-1 RNA, the effect of five anti-flt-1 ribozymes on the binding of VEGF, UPA (urokinase plasminort 29 O gen activator) and FGF (fibroblast growth factor) to their corresponding receptors were assayed. As shown in Figure 9, there was significant inhibition of VEGF binding to its receptors on cells treated with anti-flt-i ribozymes.

There was no specific inhibition of the binding of UPA and FGF to their corresponding receptors. These data strongly suggest that anti-flt-i ribozymes specifically cleave flt-i RNA and not RNAs encoding the receptors for UPA and FGF, resulting in the inhibition of flt-1 receptor expression on the surface of the cells. Thus the ribozymes are responsible for the inhibition of VEGF binding but not the binding of UPA and FGF.

Example 4: Effect of hammerhead ribozymes targeted against KDR receptor on the binding of VEGF Hammerhead ribozymes targeted to twenty one sites within KDR RNA were synthesized as described above.

Sequence of the ribozymes used are shown in Table IV; the length of stem II region is 3 bp. The hammerhead ribozymes were chemically modified such that the ribozyme 20 consists of ribose residues at five positions; U4 and U7 positions contain 2'-NH 2 modifications, the remaining nucleotide positions contain 2'-O-methyl substitutions; four nucleotides at the 5' terminus contains phosphorothioate substitutions. Additionally, the 3' end of the ribozyme contains a linked inverted abasic deoxyribose.

Referring to Figure 8, the effect of hammerhead ribozymes targeted against KDR receptor on the binding of VEGF to KDR on the surface of human microvascular endothelial cells is shown. A majority of the ribozymes tested were able to inhibit the expression of KDR and thereby were able to inhibit the binding of VEGF. As a control, the cells were treated with a ribozyme that is not targeted towards KDR RNA (irrel. RZ); there was no specific inhibition of VEGF binding. The results from this control experiment strongly suggest that the inhibi- P tion of VEGF binding observed with anti-KDR ribozymes is a ribozyme-mediated inhibition.

Example 5: Effect of ribozvmes targeted against

VEGF

receptors on cell proliferation Cell Preparation: 24-well plates are coated with 1.5% gelatin (porcine skin 300 bloom). After 1 hr, excess gelatin is washed off of the plate. Microvascular endothelial cells are plated at 5,000 cells/well (24 well plate) in 200 ml growth 10 media. The cells are allowed to grow for 18 hr 1 doubling) to yield -10,000 cells (25-30% confluent)..

Ribozyme treatment: Media is removed from the cells, and the cells are washed two times with 300 ml lX PBS: Ca 2 Mg 2 mixture.

For anti-flt-i HH ribozyme experiment (Figure 12) a complex of 500 nM ribozyme; 15 mM LFA (3:1 lipid:phosphate ratio) in 200 ml OptiMEM FCS) media was added to the cells. Incubation of cells is carried out for 6 hr (equivalent to 2-3 VEGF receptor turnovers).

For anti-KDR HH ribozyme experiment (Figure 13) a oo complex of 200 nM ribozyme; 5.25 mM LFA (3:1 lipid: phosphate ratio) in 200 ml OptiMEM FCS) media was added to the cells. Incubation of cells is carried out for 3 hr.

Proliferation: After three or six hours, the media is removed from the cells and the cells are washed with 300 ml lX PBS: Ca 2 Mg 2 mixture. Maintenance media (contains dialyzed FBS) VEGF or basic FGF at 10 ng/ml is added to the cells. The cells are incubated for 48 or 72 h. The cells are trypsinized and counted (Coulter counter). Trypan blue is added on one well of each treatment as control.

w As shown in Figure 12B, VEGF and basic FGF can stimulate human microvascular endothelial cell proliferation.

However, treatment of cells with 1358 HH or 4229 HH ribozymes, targeted against flt-i mRNA, results in a significant decrease in the ability of VEGF to stimulate endothelial cell proliferation. These ribozymes do not inhibit the FGF-mediated stimulation of endothelial cell proliferation.

Human microvascular endothalial cells were also treated with hammerhead ribozymes targeted against sites 527, 730, 3702 or 3950 within the KDR mRNA. As shown in Figure 13, all four ribozymes caused significant inhibition of VEGF-mediated induction of cell proliferation.

No significant inhibition of cell proliferation was 15 observed when the cells were treated with a hammerhead ribozyme targeted to an irrelevant RNA. Additionally, none of the ribozymes inhibited FGF-mediated stimulation of cell proliferation.

These results strongly suggest that hammerhead *e 20 ribozymes targeted against either flt-1 or KDR mRNA can specifically inhibit VEGF-mediated induction of endothelial cell proliferation.

o* Example 6: Effect of antisense oligonucleotides targeted against VEGF receptors on cell proliferation (colorimetric assay) Following are some of the reagents used in the proliferation assay: Cells: Human aortic endothelial cells (HAEC) from Clonetics®. Cells at early passage are preferably used.

Uptake Medium: EBM (from Clonetics®);1% mM Hepes; No serum; No antibiotics.

Growth Medium: EGM (from Clonetics®);FBS to 20%;1% mM Hepes.

Cell Plating: 96-well tissue culture plates are coated with 0.2% gelatin (50 ml/well). The gelatin is incubated in the wells at room temperature for 15-30 32 minutes. The gelatin is removed by aspiration and the wells are washed with PBS:Ca2*: Mg 2 mixture. PBS mixture is left in the wells until cells are ready to be added.

HAEC cells were detached by trypsin treatment and resuspended at 1.25 x 10 4 /ml in growth medium. PBS is removed from plates and 200 ml of cells 2.5 x 10' cells/well) are added to each well. The cells are allowed to grow for 48 hours before the proliferation assay.

Assay: Growth medium is removed from the wells. The cells are washed twice with PBS:Ca 2 Mg 2 mixture without antibiotics. A formulation of lipid/antisense oligonucleotide (antisense oligonucleotide is used here as a non-limiting example) complex is added to each well (100 ml/well) in uptake medium. The cells are incubated for 15 2-3 hours at 37'C in CO 2 incubator. After uptake, 100 ml/well of growth medium is added (gives final FBS concentration of After approximately 72 hours, 40 ml MTS® stock solution (made as described by manufacturer) was added to each well and incubated at 37'C for 1-3 hours, depending on the color development. (For this assay, 2 hours was sufficient). The intensity of color formation was determined on a plate reader at 490 nM.

Phosphorothioate-substituted antisense oligodeoxynucleotides were custom synthesized by The Midland Certified Reagent Company®, Midland, Texas. Following non-limiting antisense oligodeoxynucleotides targeted against KDR RNA were used in the proliferation assay: KDR 21 AS: 5'-GCA GCA CCT TGC TCT CCA TCC-3' SCRAMBLED CONTROL: 5'-CTG CCA ACT TCC CAT GCC TGC-3' As shown in Figure 10, proliferation of HAEC cells are specifically inhibited by increasing concentrations of the phosphorothioate anti-KDR-antisense oligodeoxynucleotide. The scrambled antisense oligonucleotide is not expected to bind the KDR RNA and therefore is not expected to inhibit KDR expression. As expected, there is no detectable inhibition of proliferation of HAEC cells "r 33 treated with a phosphorothioate antisense oligonucleotide with scrambled sequence.

Example 7: In vitro cleavage of flt-1 RNA by hammerhead ribozymes Referring to Figure 11A, hammerhead ribozymes

(HH)

targeted against sites 1358 and 4229 within the flt-1 RNA were synthesized as described above.

RNA cleavage assay in vitro: Substrate RNA was 5' end-labeled using [g- 32 ATP and 10 T4 polynucleotide kinase (US Biochemicals). Cleavage reactions were carried out under ribozyme "excess" conditions. Trace amount (s 1 nM) of 5' end-labeled substrate and 40 nM unlabeled ribozyme were denatured and renatured separately by heating to 90"C for 2 min and snap-cooling on ice for 10-15 min. The ribozyme and substrate were incubated, separately, at 37"C for 10 min in a buffer containing 50 mM Tris-HCl and 10 mM MgCl 2 The reaction o was initiated by mixing the ribozyme and substrate solutions and incubating at 37'C. Aliquots of 5 ml are taken at regular intervals of time and the reaction is quenched *e by mixing with equal volume of 2X formamide stop mix. The samples are resolved on 20 denaturing polyacrylamide gels. The results were quantified and percentage of target RNA cleaved is plotted as a function of time.

Referring to Figure 11B and 11C, hammerhead ribozymes targeted against sites 1358 and 4229 within the flt-1 RNA are capable of cleaving target RNA efficiently in vitro.

Example 8: In vitro cleavage of KDR RNA by hammerhead ribozymes In this non-limiting example, hammerhead ribozymes targeted against sites 726, 527, 3702 and 3950 within KDR RNA were synthesized as described above. RNA cleavage reactions were carried out in vitro essentially as described under Example 7.

34 Referring to Figures 14 and 15, all four ribozymes were able to cleave their cognate target RNA efficiently in a sequence-specific manner.

Example 9: In vitro cleavage of RNA by hammerhead ribozymes targeted against cleavage sites that are homologous between KDR and flt-1 mRNA Because flt-i and KDR mRNAs are highly homologous in certain regions, some ribozyme target sites are also homologous (see Table In this case, a single ribozyme 10 will target both flt-1 and KDR mRNAs. Hammerhead ribozyme (FLT/KDR-I) targeted against one of the homologous sites between flt-1 and KDR (flt-1 site 3388 and KDR site 3151) was synthesized as described above. Ribozymes with either a 3 bp stem II or a 4 bp stem II were synthesized.

RNA cleavage reactions were carried out in vitro essentially as described under Example 7.

Referring to Figure 16, FLT/KDR-I ribozyme with either a 3 or a 4 bp stem II was able to cleave its target RNA efficiently in vitro.

Example 10: Effect of multiple ribozvmes targeted against both flt-1 and KDR RNA on cell proliferation o* Since both flt-i and KDR receptors of VEGF are involved in angiogenesis, the inhibition of the expression of both of these genes may be an effective approach to inhibit angiogenesis.

Human microvascular endothalial cells were treated with hammerhead ribozymes targeted against sites flt-1 4229 alone, KDR 527 alone, KDR 726 alone, KDR 3950 alone, flt-1 4229 KDR 527, flt-1 4229 KDR 726 or flt-1 4229 KDR 3950. As shown in Figure 17, all the combinations of active ribozymes caused significant inhibition of VEGF-mediated induction of cell proliferation. No significant inhibition of cell proliferation was observed when the cells were treated with a catalytically inactive hammerhead ribozymes. Additionally, cells treated W with ribozymes targeted against both flt-i and KDR RNAsflt-i 4229 KDR 527; flt-i 4229 KDR 726; flt-i 4229 KDR 3950, were able to cause a greater inhibition of VEGF-mediated induction of cell proliferation when compared with individual ribozymes targeted against either flt-i or KDR RNA (see flt-i 4229 alone; KDR 527 alone; KDR 726 alone; KDR 3950 alone). This strongly suggests that treatment of cells with multiple ribozymes may be a more effective means of inhibition of gene expression.

10 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 corneal model has been used to study angiogenesis in rat and rabbit since recruitment of vessels can easily be followed in this normally avascular tissue (Pandey et al., 1995 Science 268: 567-569). In these models, a small Teflon or Hydron disk pretreated with an angiogenesis factor bFGF or 20 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).

In 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).

w 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. Again, ribozymes directed against VEGF-R mRNAs would be delivered in the Matrigel.

Several animal models exist for screening of antiangiogenic agents. These include corneal vessel formation following corneal 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) 15 or intracorneal growth factor implant (Grant et al., 1993 Diabetologia 36: 282-291; Pandey et al. 1995 supra; Zieche *o et al., 1992 Lab. Invest. 67: 711-715), vessel growth into Matrigel matrix containing growth factors (Passaniti et al., 1992 supra), female reproductive organ neovasculari- 20 zation 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 burn, endotoxin). The corneal model would utilize the intrastromal corneal 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 W and image analysis techniques. To evaluate their antiangiogenic 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 corneal 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 15 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 VIII antigen) immunohisto- 20 chemistry, Trichrome-Masson stain, or hemoglobin content.

Like the cornea, the Matrigel or Millipore® filter disk are avascular; however, it is not tissue. In the Matrigel oee or Millipore® filter disk model, ribozymes are adminiso* tered 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 cornea model, may be less problematic 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 will target only VEGFr mRNA. In other words, the involvement of other nonspecific types of stimuli in the cornea and Matrigel models is not advantageous from the standpoint of understanding the pharmacologic mechanism by which the 38 O anti-VEGFr mRNA ribozymes produce their effects. In addition, the models will allow for testing the specificity of the anti-VEGFr mRNA ribozymes by using either a- 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 15 non-specific nature, although there is a correlation between VEGF and angiogenesis in these models.

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

flt-1, KDR and/or flk-1 protein levels can be 20 measured clinically or experimentally by FACS analysis.

flt-1, KDR and/or flk-1 encoded mRNA levels will be assessed by Northern analysis, RNase-protection, primer •extension analysis and/or quantitative RT-PCR. Ribozymes 0*000 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 will be identified.

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

Patients can be treated by locally administering nucleic acids targeted against VEGF-R by direct injection.

Routes of administration may include, but are not limited to, intravascular, intramuscular, subcutaneous, intra- W articular, aerosol inhalation, oral (tablet, capsule or pill form), topical, systemic, ocular, intraperitoneal and/or intrathecal delivery.

Example 11: Ribozyme-mediated inhibition of angiogenesis in vivo The purpose ot this study was to assess the antiangiogenic activity of hammerhead ribozymes targeted against flt-i 4229 site in the rat cornea model of VEGF induced angiogenesis (see above). These ribozymes have 10 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 5 I-labeled) VEGF binding in cultured endothelial cells and produce a dose-dependent decrease in VEGF induced endothelial cell proliferation in these cells (see Examples 3-5 above). The catalytically inactive forms of these ribozymes, wherein the ribozymes can only bind to the RNA but cannot catalyze RNA cleavage, fail to show 20 these characteristics. 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 rhodaminelabeled 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 mM 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 was 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-i 4229 (786 pM)- Active b. flt-1 4229 (736 jM)- Inactive 2. Experimantal solutions/groups: Group 1 Solution 1 Control VEGF solution: 30 MM in 82mM Tris base Group 2 Solution 2 flt-i 4229 (1 pg/4L) in 30 jM VEGF/82 mM Tris base Group 3 Solution 3 flt-1 4229 (10 yg/AL) in 30 iM VEGF/82 mM Tris base Group 4 Solution 4 No VEGF, flt-i 4229 (10 pg/iL) 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 W 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 pM) was prepared from a stock of 0.82 pg/pL in 50 mM Tris base. 200 AL of VEGF stock was concentrated by speed vac to a final volume of 60.8 pL, for a final concentration of 2.7 pg/pL or 60 pM.

Six 10 pL aliquots was prepared for daily mixing. 2X solutions for VEGF and Ribozyme was stored at 4"C until 10 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.

e 4. Surgical Solutions: Anesthesia: 15 stock ketamine hydrochloride 100 mg/mL stock xylazine hydrochloride 20 mg/mL stock acepromazine 10 mg/mL Final anesthesia solution: 50 mg/mL ketamine, mg/mL xylazine, and 0.5 mg/mL acepromazine 5% povidone iodine for opthalmic surgical wash 2% lidocaine (sterile) for opthalmic administration (2 drops per eye) sterile 0.9% NaCI for opthalmic irrigation Surgical Methods: Standard surgical procedure as described in Pandey et al., supra. Filter disks were incubated in 1 yL of each solution for approximately 30 minutes. prior to implantation.

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 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.

Results are graphically represented in Figure 18. As shown in the figure, flt-1 4229 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 15 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, the mechanism of inhibition appears to be by the binding and S 20 cleavage of target RNA by ribozymes.

Diagnostic uses Ribozymes of this invention may be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of flt-1, KDR and/or flk-1 RNA in a cell. The close relationship between ribozyme 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 threedimensional structure of the target RNA. By using multiple ribozymes described in this invention, one may 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 ribozymes may 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 V may be defined as important mediators of the disease.

These experiments will lead to better treatment of the disease progression by affording the possibility of combinational therapies multiple ribozymes targeted to different genes, ribozymes coupled with known small molecule inhibitors, or intermittent treatment with combinations of ribozymes and/or other chemical or biological molecules). Other in vitro uses of ribozymes of this invention are well known in the art, and include detection of the presence of mRNAs associated with flt-1, KDR and/or flk-1 related condition. Such RNA is detected :by determining the presence of a cleavage product after treatment with a ribozyme using standard methodology.

In a specific example, ribozymes which can cleave 15 only wild-type or mutant forms of the target RNA are used for the assay. The first ribozyme is used to identify wild-type RNA present in the sample and the second ribozyme will be used to identify mutant RNA in the sample.

As reaction controls, synthetic substrates of both wild- 20 type and mutant RNA will be cleaved by both ribozymes to demonstrate the relative ribozyme efficiencies in the reactions and the absence of cleavage of the "nontargeted" RNA species. The cleavage products from the synthetic substrates will also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus each analysis will require two ribozymes, two substrates and one unknown sample which will be combined into six reactions. The presence of cleavage products will be 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 flt-1, KDR and/or flk-1) is adequate to establish 44 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 will be correlated with higher risk whether RNA levels are compared qualitatively or quantitatively.

Other embodiments are within the following claims.

**o *oo o*ooo Table I Characteristics of Ribozvmes 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 10 T4, blue-green algae, and others.

RNAseP RNA (Ml RNA) Size: -290 to 400 nucleotides RNA portion of a ribonucleoprotein enzyme. Cleaves tRNA precursors to form mature tRNA.

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

Hammerhead Ribozyme *o Size: -13 to 40 nucleotides.

Requires the target sequence UH immediately 5' of the 20 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 10 (Figure 4).

Neurospora VS RNA Ribozvme 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 Table II: Human .fltl VEGE Receptor- Hammerhead Ribozyme and Substrate Sequence 20 nt.

Position 13 15 23 43 54 62 97 98 HH Ribozyme Substrate GCCGAGAG CUGAUGA X GGAGCCGA CUGAUGA X GAGGAGCC CUGAUGA X CCGGGGAG CUGAUGA X CUGCCGGG CUGAUGA X CCCGCUCC CUGAUGA X GAGCCCCG CUGAUGA X CUGCACCC CUGAUGA X CCCCGGGU CUGAUGA X UCCCCGGG CUGAUGA X GAA AGUGUCCG GAA AGGAGUGU GAA AGAGGAGU GAA AGCCGAGA GAA AGGAGCCG GAA AGCCGCCG GAA AGCCCGCU GAA AGCCCCGG GAA AUCCUCGC GAA AAUCCUCG CGGACACUC CUCUCGGC ACACUCCUC UCGGCUCC ACUCCUCUC GGCUCCUC UCUCGGCUC CUCCCCGG CGGCUCCUC CCCGGCAG CGGCGGCUC GGAGCGGG AGCGGGCUC CGGGGCUC CCGGGGCUC GGGUGCAG GCGAGGAUU ACCCGGGG CGAGGAUULA CCCGGGGA 113 CAGGAGAC CUGAUGA X GAA ACCACUUC GAAGUGGUU

GUCUCCUG

116 118 145 185 198 201 240 246 10 255 260 276 294 301 306 307 309 317 319 322 323 328 329 335 336 343 355 356 357 375 400 402

AGCCAGG,

CCAGCCA(

CGCGCCCI

GGCCGCC)

CGGCCAA(

CCCCGGCC

GUGAGCGC

ACCAUGGI

CAGUAGCL

UGUCCCAC

CACAGCAC

AGACAGCU

GAGAAGCA

CCUGUGAG

UCCUGUGA

GAUCCUGU

CUGAACUA

ACCUGAAC

UGAACCUG

UTUGAACCU

UAAUUUG

UUAAUUUU

GAUCUUUU

GGAUCULU

CAGUUCAG

GCCUUTUUA

UGCCUUU

GUGCCUUUT

GCULJGCAU

GCAUTUGGA

CUGCAUUG

k. CUGAUGA 3 CUGAUGA J CUGAUGA k. CUGAUGA

CUGAUGA

CUGAUGA

7CUGAUGA J CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA Y CUGAUGA Y~ CUGAUGA Y CUGAUGA X CUGAUGA X KC GAA ACAACCAC K GAA AGACAACC ~GAA AGCGCCCG CGAA AGUCCGUC C GAA ACCCGGCC I GAA ACGACCCG CGAA ACGCGGCC GAA AGCGCGAC GAA ACCAUGGU GAA AGCUGACC GAA ACCCCGGU GAA AGCAGCGC GAA ACAGCUGA GAA AGCAGACA GAA AAGCAGAC GAA AGAAGCAG GAA AUCCUGUG GAA AGAUCCUG GAA ACUAGAUC GAA AACUAGAU GAA ACCUGAAC GAA AACCUGAA GAA AUUUUGAA GAA AAUUtJUGA GAA AUCUUUJUA GAA ACUCAGUU GAA AACUCAGU GAA AAACUCAG GAA AUGUGCUG GAA AUG CAGUG GAA AGAUGCAG

GUGGUUGU

GGUUGUCU

CGGGCGCU

GACGGACU

GGCCGGGUi

CGGGUCGU

GGCCGCGU(

GUCGCGCU(

ACCAUGGUC

GGUCAGCUI

ACCGGGGUC

GCGCUGCUC

UCAGCUGUC

UGUCUGCUL

GUCUGCUUC

CUGCUUCUC

CACAGGAUC

CAGGAUCUA

GAUCUAGUJ

AUCUAGUUC

GUUCAGGUU

UUCAGGUUC

UUCAAAAUU

UCAAAAUUA

UAAAAGAUC

AACUGAGUU

ACUGAGUUU

CUGAGUUUEA

CAGCACAUC

CACUGCAUC

CUGCAUCUC

C UCCUGGCU C CUGGCUGG C AGGGCGCG

CUGGCGGCC

GUUGGCCG

J GGCCGGGG 2GCGCUCAC 7ACCAUGGU

AGCUACUG

CUGGOACA

CUCCUGUG

-AGCUGUCU

*UGCUUCUC

rCUCACAGG

UCACAGGA

ACAGGAUC

UAGUTUCAG

GUUCAGGU

CAGGUUCA

AGGLTUCAA

CAAAAUUA

AAAAUUAA

AAAAGAUC

AAAGAUCC

CUGAACUG

UAAAAGGC

AAAAGGCA

AAAGGCAC

AUGCAAGC

UCCAAUGC

CAAUGCAG

427 AGACCAUU CUGAUGA X GAA AUGGGCUG CAGCCCAUA AAUGGUCU 434 CAGGCAAA CUGAUGA X GAA ACCAUtJUA UAUGCUUCU UAAAUGGUC

UUUGCCUG

436 437 454 477 481 485 512 513 10 520 523 524 525 530 15 541 560 561 563 575 577 579 585 589 592 593 614 621 623 625 627 629 630 631

UUCAGGCI

UUUCAGGC

GCUUUCCI

GAUUUAGL

GGCAGAUJ

CACAGGCPA

UACUGCAG

GUACUGCA

GGUTUAAAG

CAAGGUTUA

UCAAGGUUJ

UTUCAAGGU

CUGUGIJUC

GUUUGCUUL

AGCUGUAG

CAGCUGUA

UGCAGCUG

CAGCUAGA

UACAGCUA

GGUACAGC

GAAGUAGG

CUUUGAAG

CUUCUUUJG

UCUUTCUUUT

AGAUUGCA

AAUAUAUA

UAAAUAUA

AAUAAAUA

CUAAUAAA

CACUAAUA

UCACUAAU

AUCACUAA

CUGAUGA

CUGAUGA

J CUGAUGA

TCUGAUGA

FCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA CUGAUGA CUGAUGA GAA AGACCAUU GAA AAGACCAU GAA ACUCACCA GAA AUG CUCAG GAA AGUTUAUGC GAA AUUUAGUU GAA AUUTGUUUG GAA AAUJUGUUU GAA ACUGCAGA GAA AGUACUGC GAA AAGUACUG GAA AAAGUACU GAA AGGUUA1A GAA AGCUGUGU GAA AGCCAGUG GAA AAGCCAGU GAA AGAAGCCA GAA AUUUGCAG GAA AUAUUJLGC GAA AGAUAUUU GAA ACAGCUAG GAP. AGGtJACAG GAP. AGUAGGUA GAP. AAGUAGGU GAA AtJUCUGUU GAP. AUUGCAGA GAP. AGAUUGCA GAP. AUAGAUUG GAA AUAUAGAU GA. AUAUAUAG GAP. AAUAUAUA GAP. AAAUAUAU

AAUGGUCUL

AUGGUCUUL

UGGUGAGU;P

CUGAGCAUP

GCAUAACUP

AACUAAAUC

CAAACAAUU

AAACAAUUC

UCUGCAGUA

GCAGUACUU

CAGUACUUU

AGUACUUJA

ULJUAACCUJ

ACACAGCUC

CACUGGCUU

ACUGGCUUC

UGGCUJCUA

CUGCAAAUA

GCAAAUAUC

AP.AUAUCUA

CUAGCUGUA

CUGUACCUA

UACCUACUU

ACCUACUTUC

AACAGAP.UC

UCUGCAAUC

UGCAAUCUA

CAAUCUAUA

AUCUAUAUA

CUAUAUAUU

UAUAUAUUU

AUAUAULTUA

J UGCCUGAA

JGCCUGAAA

AGGAAAGC

ACUAAAUC

AAUCUGCC

UGCCUGUG

CUGCAGUA

UGCAGUAC

CUUTUAACC

UAACCUUG

AACCUUGA

ACCUUGAA

GAACACAG

AAGCAAAPC

CUACAGCU

UACAGCUG

CAGCUGCA

UCUAGCUG

UAGCUGUA

GCUGUACC

CCUACUTUC

CUUCAAAG

CAAAGAAG

AAP.GAAGA

UGCAAUCU

UAUAUAUU

UAUAUUUA

UAUUTUAUU

UUUAUUAG

UAUUAGUG

AULJAGUGA

UUAGUGAU

633 GUAUCACU CUGAUGA X GAA AUAAAUAU AAUAUAU~~ AUAUUUAUU AGUGAUAC 46 0, 0 s* 0#60 634 640 646 652 653 654 657 66S 10 675 684 68S 687 711 714 717 718 729 730 20 734 739 744 750 751 754 755 756 764 76S 766 771 778

UGUAUCA(

UCUACCUC

GAAAGGUC

CUCUACGI

UCUCUACC

AUCUCUAC

UACAUCUC

UTUCACUC

AUUUCGGC

AUGUGUAU

CAUGUGUA

GUCAUGUG

GGAAUGAC

CAGGGAAU

CGGCAGG4G

CCGGCAGG

GGUGACGU

AGGUGACG

UGUTUAGGU

AGUGAUGU

GUAACAGU

UUUAAAGU

TJUUUAAAG

CUUUUIJUA

ACUUUULU

AACUUUUU

CAAGUGGA

UCAAGUGG

GUCAAGUG

AAAGUGUC

AGGGAUCA

:CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAU.GA

CtJGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA2 CUGAUGA2

CUGAUGA)

CGAA AAUAAAUA C GAA AUCACUAA GAA ACCUGUAU GAA AGGUCUAC GAA AAGGUCUA GAA AAAGGUCU GAA ACGAAAGG GAA ACAUCUCU GAA AUUUCACU GAA AUULJCGGG GAA AAUUUCGG GAA AUAAUUUC GAA AGCUCCCU GAA ACGAGCUC GAA AUGACGAG

GAAAAUGACGA

GAA ACCCGGCA GAA AACCCGGC GAA ACGUAACC GAA AGGUGACG GAA AUGUUAGG GAA ACAGUGAU GAA AACAGUGA GAA AGUAACAG GAA AAGUAACA GAA AAAGUAAC GAA ACUUUUUU GAA AACJUUTEJ GAA AAACUU-U GAA AGUGGAAA GAA AGUGUCAA UAtJUUAUUI

UUAGUGAU;

AUACAGGU;z

GUAGACCUL

UAGACCUUL

AGACCUUUC

CCUtJUCGUA

AGAGAUGUA

AGUGAAAUC

CCCGAAAUU

CCGAAAUUA

GAAAUTJAUA

AGGGAGCUC

GAG CUCGUC

CUCGUCAUU

UCGUCAUUC

UGCCGGGtU

GCCGGGUUA

GGUUACGUC

CGUCACCUA

CCUAACAUC

AUCACUGUU

UCACUGUUA

CUGUTUACUU

UGUYUACULU

GUUACUUUA

AAAAAAGUU

AAAAAGUUU

AAAAGUUTUC

UUUCCACUU

UUEGACACUJ

kGUGAUACA

CAGGUAGA

GACCUUtUC

TUCGUAGAG

FCGUAGAGA

GUAGAGAU

GAGAUGUA

CAGUGAAA

CCCGAAAU

AUACACAU

UACACAUG

CACAUGAC

GUCAUUCC

AUUCCCUG

CCCUGCCG

CCUGCCGG

ACGUCACC

CGUCACCU

ACCUAACA

ACAUCACU

ACUGtJUAC

ACUUTUAAA

CUTJUAAAA

UAAAAAAG

AAAAAAGU

AAAAAGLU

UCCACUUG

CCACUUJGA

CACUTUGAC

GACACUUUJ

UGAUCCCU

S

S. S 0 .5555

S

S

779 CAGGGAUC CUGAUGA X GAA AAGUGUCA UAAUUGUCU UGACACUUU GAUCCCUG 0 00.0* 0* 783 801 804 814 824 825 828 831 833 10 84'5 855 861 862 882 892 893 896 898 908 910 912 919 931 936 939 945 951 969 974 975 978 979

CCAUCAGG

UCCCAGAU

CUGUCCCA

GCCCIJUUC

AUAUGAUG

GAUAUGAU

UUUGAUAU

GCAUUGA

UUGCAUU

UTJCUUUG

AGAAGCCC

CAGGUCAG

ACAGGUCA

UGCCCAUU

CIJUAUACA

UCUUAUAC

LTIGUCUUA

GUUUGUCU

GUGUGAGA

AUGUGUGA

CGAUGUGU

GGUUUGUC

UAUGAUUTG

ACAUCUAU

UGGACAUC

CUULTUUG

GGUGUGCU

AGUAAUUU

CUCUAAGU

CCUCUAAG

UGGCCUCU

AUGGCCUC

CUGAUGA

CUGAUGA

*CUGAUGA

*CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA,

CUGAUGA:

CUGAUGA:

CUGAUGAI

CUGAUGA:.

GAA AUCAAAGU GAA AUGCGUUU GAA AUUAUGCG GAA ACUGUCCC GAA AGCCCUUU GAA AAGCCCUU GAA AUGAAGCC GAA AUGAUGAA GAA AUAUGAUG GAA ACGUTUGCA GAA AUtJUCUTU GAA AGCCCUAU GAA AAGCCCUA GAA ACUGUUGC GAA AUGCCCAU GAA AAUGCCCA GAA ACAAAUGC GAA AUACAAAU GAA AGUUUGUC GAA AUAGUTUUG GAA AGAUAGUU GAA AUGUGUGA GAA AUUGGUUU GAA AUUGUAUU GAA AUGAUTUGU GAA ACAUCUAU GAA AUUUGGAC GAA ACUGGGCG GAA AUUUGACU GAA AAUUUGAC GAA AGUAAUUU GAA AAGUAAUU ACUUUGAuc

AAACGCAUP

CGCAUAAUC

GGGACAGUA

AAAGGGCUU

AAGGGCUUC

GGCUUCAUC

UUCAUCAUA

CAUCAUAUC

UGCAACGUA

AAAGAAAUA

AUAGGGCUU

UAGGGCUUC

GCAACAGUC

AUGGGCAUIJ

UGGGCAUUU

GCAUUUGUA

AUTUUGUAUA

GACAAACUA

CAAACUAUC

AACUAUCUC

UCACACAUC

AAACCAAUA

AAUACAAUC

ACAAUCAUA

AUAGAUGUC

GUCCAAAUA

CGCCCAGUC

AGUCAAAUU

GUCAAAUUA

AAAUUACUU

AALUACUUA

CCUGAUGG

LAUCUGGGA

UGGGACAG

IGAAAGGGC

CAUCAUAU

AUCAUAUC

AUAUCAAA

UCAAAUGC

AAAUGCAA

CAAAGAAA

GGGCUUCU

CUGACCUG

UGACCUGU

AAUGGGCA

UGUAUAAG

GUAUAAGA

UAAGACAA

AGACAAAC

UCUCACAC

UCACACAU

ACACAUCG

GACAAACC

CAAUCAUA

AUAGAUGU

GAUGUCCA

CAAAUAAG

AGCACACC

AAAUTUACU

ACtJUAGAG

CUUAGAGG

AGAGGCCA

GAGGCCAU

988 GACAAGAG CUGAUGA X GAA AUGGCCUC GGCAACCUU GAGGCCAUA CUCUUGUC 991 993 996 999 1003 1006 1012 1018 1022 10 1035 1036 1051 1052 1069 1078 1079 1083 1095 1108 1109 1122 1124 1125 1127 1134 1135 1137 1138 1141 1143 1173 1174

GAGGACAX

TJUGAGGA(

CAAUUGA(

GUACAAUI

AGCAGUAC

GGUAGCAC

GGGAGUGC

GUUCAAGC

UCGUGIJUC

GUCAUU)TJC

GGUCAUUUJ

AUCAGGGU

CAUCAGGG

AGCUCUCU

CCUtJACGG

GCCUUACG

CGUCGCCU

CUUUTGGUC

GGCAUGGG

UGGCAUGG

CUGUAGAA

CACUGUAG

ACACUGUA

GAACACUG

AUAGUAAG

AAUAGUAA

UCAAUAGU

GUCAAUAG

LWGUCAA

AtUUUGUC CAAGUAtJA

ACAAGUAU

kCUGAUGA 2CUGAUGA

SCUGAUGA

J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA)

CUGAUGA

CUGAUGA CUGAUGA Y~

CUGAUGA',X

CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X X GAA AGUAUGGC X GAA AGAGUAUG X GAA ACAAGAGU K GAA AGGACAAG K GAA AUUGAGGA K GAA ACAAUTUGA K GAA AGCAGUAC C GAA AGUGGUAG C GAA AGGGAGUG [GAA ACUCUCGU GAA AACUCUCG GAA ACUCCAGG GAA AACUCCAG GAA ALUJULTUUU GAA AGCUCUCU GAA AAGCUCUC GAA ACGGAAGC GAA AUtJCGUCG GAA AULJGCLUUJ GAA AAUUGCUU GAA AUGUUGGC GAA AUAUGUUG GAA AAUAUGUU GAA AGAAUAUG GAA ACACUGUA GAA AACACUGU GAA AGAACACU GAA AAGAACAC GAA AGUAAGAA GAA AUAGUAAG GAA AGUCCUUU GAA AAGUCCUUI

GCCAUACU

CAUACUCT

ACUCUILJGU,

CUUGUCCU

UCCUCAALTI

-UCAAUUGUj

GUACUGCU)

CUACCACUC

CACUCCCUL

ACGAGAGUL

CGAGAGUUC

CCUGGAGUL

CUGGAGUUP

AAAAAAAUP

AGAGAGCUU

GAGAGCUUC

GCUUCCGUA

CGACGAAUJ

AAAGCAAUU

AAGCAALTTJC

GCCAACAUA

CAACAUALU

AACAUAUUC

CAUAUUCUA

UACAGUGU

ACAGUGUU1C AGUGUtJCUU

GUGLUJCUUA

UUCLUACUA

CUIJACUALU

AAAGGACUU

AAGGACUEJ

C UUGUCCUC UI GUCCUCAA C CUCAAUUG C AAUUGUAC J GUACUGCU

~CUGCUACC

\CCACUCCC

CCUUGAAC

JGAACACGA

JCAAAUGAC

AAAUGACC

JACCCUGAU

CCCUGAUG

AGAGAGCU

CCGUAAGG.

CGUAAGGC

AGGCGACG

GACCAAAG

CCCAUGCC

C CAUG CCA

UUCUACAG

CUACAGUG

UACAGUGU

CAGUGUTUC

CLUACUAU

LTUACUA-U

ACUAUTUGA

CUAUUGAC

LUGACAAA

GACAAAAU

UAUACUUG

AUACLUIJGU

1175 GACAAGUA CUGAUGA X GAA AAAGUCCU AGGACUUUA UACUTJGUC 1177 1180 1183 1188 1202 1205 1206 1211 1215 10 1216 1223 1231 123 3 123S 15 1240 1247 1248 1251 1264 1281 1290 1304 1306 1307 1314 1316 1318 1334 1335 1336 1340 1350

ACGACAA(

UACACGAC

CCUUACA(

CCACUCCL

AUTUUGAAL

CAGAUUUC

ACAGAUUJ

UGUUAACP.

GAGGUGUL

UGAGGUGU

UAUGCACU

AUCAUAUA

UUAUCAUA

CUUIJAUCA

GAAUGCUUI

CAGUGAUG

ACAGUGAU

UUCACAGU

CUGULTUUC

ACGGUUUC

UTUGCCAGC

GCCGGUAA

GAG CCGGU

AGAGCCGG

UUCAUAGA

CUUUCAUA

CACUUUCA

GCGAGGGA

GGCGAGGG

CGGCGAGG

CUUCCGGC

AACCAUAC

3CUGAUGA

CUGAUGA

CUGAUGA

J CUGAUGA J CUGAUGA

;CUGAUGA

r CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA I CUGAUGA C GAA AUAAAGUC CGAA AGUAUAAA C GAA ACAAGUAU GAA ACACGACA GAA AUGGUCCA GAA AUGAUGGU GAA AAUGAUGG GAA AUUUGAAU GAA ACAGAUUU GAA AACAGAUU GAA AGGUGUUA GAA AUG CACUG GAA AUAUGCAC GAA AUAUAUGC GAA AUCAUAUA GAA AUG CUUUA GAZA AAUGCUUU GAA AUGAAUGC GAA AUGUUJUCA GAZA AGCACCUG GAZA ACGGUJUC GAA ACCGCUUJG GAA AGACCGCU GAA AAGACCGC GAA AGCCGGUA GAA AGAGCCGG GAA AGAGAGCC GAA AUG CCUUC GAA AAUGCCUU GAA AAAUGCCU GAA AGGGAAAU GAA ACUtJCCGG GACUUIAU1

UTUUAUACI.

AUACUJGU(

UGUCGUGU;

UGGACCAUC

ACCAUCAUL

CCAUCAUUC

AUUCAAAUC

AAAUCUGUU

AAUCUGUUA

UAACACCUC

CAGUGCAUA

GUGCAUAUA

GCAUAUAUA

UAUAUGAUA

UAAAGCAUU

AAAGCAUUC

GCAUUCAUC

UGAAACAUC

CAGGUGCU

GAAACCGUA

CAAGCGGUC

AGCGGUCUU

GCGGUCUUA

UACCGGCUC

CCGGCUCUC

GGCUCUCUA

GAAGGCAUU

AAGGCAUU

AGGCAUUUJTC

AUUUCCCUC

CCGGAAGtU k. CUUGUCGU

JGUCGUGUA

GUGUAAGG

LAGGAGUGG

AUUCAAAU

ICAAAUCUG

AAAUCUGU

UGUUJAACA

AACCUC

ACACCUCA

AGUGCAUA

UAUAUGAU

UAUGAUAA

UGAUAAAG

AAGCAUTUC

CAUCACUG

AUCACUGU

ACUGUGAA

GAAAACAG

GAAACCGU

GCUGGCAA

UTUACCGGC

ACCGGCUC

CCGGCUCU

UCUAUGAA

UAUGAAAG

UGAAAGUG

UCCCUCGC

CCCUCGCC

CCUCGCCG

GCCGGAAG

GUAUGGUUI

1353 UUUAACCA CUGAUGA X GAA ACAACUUC GAAGUUGUA UGGUUAAA

C

C

1358 1359 1370 1371 1388 1393 1397 1399 1400 10 1405 1412 1415 1418 1419 1422 1423 1425 1434 1456 1457 1459 1464 1466 1476 1484 1493 1494 1495 1503 1513 1515 1518 1521.

UCGCAGGU CUGAUGA GUCGCAGG CUGAUGA AG CGAG CA CUGAUGA

C

CAAAUAGC

GAGUCAAA

ACGAGUCA

CACGAGUC

GUAGCCAC

UUAACGAG

UAAUtJAAC

UGAUAAUJ

UUGAUAAU

UCCUUGAU

GUCCUULGA

ACGUCCUU

UCUIJCAGU

GALUGUAU

AGAtJUGUA

CAAGAUUG

CUCAGCAA

UGCUCAGC

GACUGUUU

ACACAULU I GGUUtJUUA

AGGUUUUU

GAGGUUUU

GUGGCAGU

GACAAUUA

UUGACAAU

ACAUUGACC

UUCACAUU C

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CAUCUUUU CUGAUGA X GAA ACCAUACA CCAUCUUJ CUGAUGA X GAA AACCAUAC X GAA ACCCAUCU X GAA AACCCAUC X GAA AUUUCUCA X GAA AGCAGAUU X GAA AGCGAGCA X GAA AUAGCGAG X GAA AAUAGCGA X GAA AGUCAAAU X GAA AGCCACGA X GAA AGUAGCCA X GAA ACGAGUAG X GAA AACGAGUA X GAA AUUAACGA X GAA AAUEJAACG X GAA AUAAUTUAA X GAA ACGUCCUUJ X GAA AUUCCCUG X GAA AAUUCCCU X GAA AUAALTUCC X GAA AUUGUAUA X GAA AGAUUGUA X GAA AUGCUCAG X GAA ACUGUTUUU X GAA ACACAUUU K GAA AACACALU UGUAUGGUTU

AAAAGAUG

GUAUGGUUA

AAAGAUGG

AGAUGGGtJU

ACCUGCGA

GAUGGGUUA

CCUGCGAC

UGAGAAAUC

UGCUCGCU

AAUCUGCUC

GCUAJEJLG

UGCUCGCUA

IJUUGACUC

CUCGCUAUU

UGACUCGU

UCGCUAUUU

GACUCGUG

AUUUGACUC

GUGGCUAC

UCGUGGCUA

CUCGUUAA

UGGCUACUC GUtJAAUUA CUACUCGUU AALTUAUCA UACUCGUUA

AUUAUCAA

UCGUUAAUU AUCAAGGA CGUtJAAUUA

UCAAGGAC

UUAAUUAUC

AAGGACGU

AAGGACGUA ACUGAAGA CAGGGAAtJU

AUACAAUC

AGGGAAUUA UACAAUCU GGAALUAUA CAAUCIJUG UAUACAAUC UUGCUGAG UACAAUCUU

GCUGAGCA

CUGAGCAUA

AAACAGUC

AAAACAGUC AAAUGUGU AAAUGUGUU UAAAAACC AAUGUGUUU

AAAAACCU

AUGUGLUUJA AAAACCUC AAAAACCUC

ACUGCCAC

CUGCCACUC

UAAUTUGUC

GCCACUCUA ALUUGUCAA ACUCUAAUU

GUCAAUGU

CUAAUUGUC AAUGUGAA CUGAUGA X GAA AAACACAU :UGAUGA X GAA AGGUULUU :UGAUGA X GAA AGUGGCAG 'UGAUGA X GAA AGAGUGGC UGAUGA X GAA AUUAGAGU UGAUGA X GAA ACAAUUAG

S.

S S S S S

S.

S

S

S

555555 1539 1540 1541 1556 1559 1562 1563 1564 1576 10 1578 1580 1602 1609 1612 1619 1624 1626 1630 1636 20 1641 1649 1650 1663 1669 1672 1675 1676 1694 1695 1696 1699 1700 1705

UUTUUCGUA

CUUUIJCGU

CCUUUUICG

GAAACGAU

CUGGAAAC

GGUCUGGA

GGGUCUGG

CGGGUCUG

UGGGUAGA

AGUGGGUA

CCAGUGGG

CAAGUCAG

UGCGGUAC

AUAUGCGG

GGAUACCA

tJUGAGGGA GGUtJGAGG

UGUAGGLU

CLUGALUUG

AACCACU

GGUGCCAG

GGGUGCCA

ALUAUGGU

GGAAUGAU

UUCGGAAU

UGCUUCGG

tJUGCLUUCG

UGGAACAA

UUGGAACA

AUUGGAAC

AUUAUUGG

CAUUAUJG

CUCUUCAU

CUGAUGA X GAA AUCUGGGG CUGAUGA X GAA AAUCUGGG CUGAUGA X GAA AAAUCUGG CUGAUGA X GAA ACACGGCC CUGAUGA X GAA AUGACACG CUGAUGA X GAA ACGAUGAC CUGAUGA X GAA AACGAUGA CUGAUGA X GAA AAACGAUG CUGAUGA X GAA AGCCGGGU CUGAUGA X GAA AGAGCCGG CUGAUGA X GAA AGAGAGCC CUGAUGA X GAA AUTUUGUCU CUGAUGA X GAA AGUCAGGA CUGAUGA X GAA ACAAGUCA CUGAUGA X GAA AUGCGGUA CUGAUGA X GAA ACCAUAUG CUGAUGA X GAA AUACCAUA CUGAUGA X GAA AGGGAUAC CUGAUGA X GAA AGGUUGAG CUGAUGA X GAA AUUGUAGG CUGAUGA X GAA ACCACUUG CUGAUGA X GAA AACCACUU CUGAUGA X GAA ACAGGGGU CUGAUGA X GAA AUGGtJUAC CUGAUGA X GAA AUUAUGGU CUGAUGA X GAA AUGAuuAU CUGAUGA X GAA AAuGAuuA CUGAUGA X GAA AGUCACAC CUGAUGA X GAA AAGUCACA CUGAUGA X GAA AAAGUCAC CUGAUGA X GAA ACAAAAGU CUGAUGA X GAA AAcAAAAG CUGAUGA X GAA AUTUGGAA.C CCCCAGAUU UACGAAAA CCCAGAUUU ACGAAAAG CCAGAUUUA CGAAAAGG GGCCGUGUC AUCGUUUC CGUGUCAUC GUUUCCAG GUCAUCGUU UCCAGACC UCAUCGULJU CCAGACCC CAUCGUTUUC CAGACCCG ACCCGGCUC UCUACCCA CCGGCUCUC UACCCACU GGCUCUCUA CCCACUGG AGACAAAUC CUGACUUG UCCUGACJU GUACCGCA UGACUUGUA CCGCAUAU UACCGCAUA UGGUAUCC CAUAUGGUA UCCCUCAA UAUGGUAUC CCUCAACC GUAUCCCUC AACCUACA CUCAACCUA CAAUCAAG CCUACAAUC AAGUGGUU CAAGUGGUtJ CUGGCACC AAGUGGUtJC UGGCACCC ACCCCUGUA ACCAUAAU GUAACCAUA AUCALUCC ACCAUAAUC AUUCCGAA AUAAUCAUTU CCGAAGCA UAAUCALTUC CGAAGCAA GUGUGACUU UUTGUUCCA UGUGACUUU UGUUCCAA GUGACUUUU GUUCCAAU ACUUUGUtJ CCAAUAAU CUULUUGUTUC CAAUAAUG GUUCCAAUA AUGAAGAG 1715 GGAUAAAG CUGAUGA X GAA ACUCUUCA UAGGCCUAC UGAAGAGUC CUUUAUCC 1718 1719 1720 1722 1755 1764 1768 1782 10 1785 1798 1807 1814 1818 1829 1831 1836 1837 1838 1845 1847 1851 1852 1857 1861 1862 1867 1872 1893 1898 1899 1900

CCAGGAUJ

UCCAGGAI

AUCCAGGI

GCAUCCAC

AUGCUCUC

CGCUGAGt

CAUGCGCL

CCUULCUAtU UuUCCUC

AGCCAUCLJ

CAAGGUGC

CCACAACC

UCAGCCAC

AAAUUCUA

AGAAAUTUC

AUUCCAGA

GAUUCCAG

AGAUTUCCA

CAAAUGUA

UGCAAAUG

GCUAUGCA

AGCUAUGC

UUGGAAGC

UUUAUUGG

CUUUAUUG

CCCAACUU

ACAGUCCC

UAAAAGCU

UGAUAUAA

GUGAUAUA

UGUGAUAU

k~ CUGAUGA J CUGAUGA kCUGAUGA

CUGAUGA

CUGAUGA

J CUGAUGA

ICUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA)

CUGAUGA

GAI

GAI

GA7 GA7

GA;

GAP

GAP

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

AGGACUCU

~AAGGACUC

SAAAGGACU

AUAAAGGA

AUtJCUGUU

AUGCUCUC

AGUGAUGC

AUUGCCAU

AUUAUTUGC

AUUCUUUC

AGCCAUCU

AGGUGCUA

ACCAAGGU

AGUCAGCC

AGAGUCAG

AUJUCUAGA

AAUUCUAG

AAAUUCUA

AUUCCAGA

AGAUUCCA

AUGUAGAU

AAUGUAGA

AUGCAAA.U

AGCUAUGC

AAGCUAUG

AUTUGGAAG

ACUUTUAUU

AUGUUJICU

AGCUJUAUG

AAGCUUAU

AAAGCUUA

AGAGUCCU

GAGUCCULT

AGUCCUUM

UCCUUtJAU(

AACAGAAUI

GAGAGCAUC

GCAUCACUC

AUGGCAAUI

GCAAUAAU;

GAAAGAAUI

AGAUGGCUP

UAGCACCUL

ACCUUGGUU

GGCUGACUC

CUGACUCUA

UCUAGAAUU

CUAGAAUJIJ

UAGAAUUUC

UCUGGAAUC

UGGAAUCUA

AUCUACAUU

UCUACAUUJ

AUUTUGCAUA

GCAUAGCUTJ

CAUIAGCUUJC

CUUCCAAUA

AAUAAAGUU

AGAAACAUA

CAUAAGCUU

AUAAGCLUU

UAAGCUULUJ

UI UAUCCUGG JI AUCCUGGA

UCCUGGAU

_CUGGAUGC

J GAGAGCAU

ACUCAGCG

AGCGCAUG

SAUAGAAGG

GAAGGAAA

AGAUGGCU

GCACCUUG

GGUUGUGG

GUGGCUGA

UAGAAUtJ

GAAIJUUCU

UCUGGAAU

CUGGAAUC

UGGAAUCU

UACAUUUG

CAUUUGCA

UGCAUAGC

GCAUAGCU

GCIJUCCAA

CCAAUAAA

CAAUAAAG

AAGUUGGG

GGGACUGU

AGCUUJUUA

UTUAUAUCA

UAUAUCAC

AUAUCACA

1901 CUGUGAUA CUGAUGA X GAA AAAAGCUUt AAGCUUUUA UAUCACAG '0.0 .00.S 0. 0 1903 1905 1925 1926 1927 1932 1933 1937 1976 10 1978 1986 1987 1994 1995 1997 1998 2000 2010 2011 20 2014 2019 2020 2021 2022 2034 2035 2038 2054 2059 2061 2062 2082 2086

AUCUGIJG;

ACAUCUGL

TJAACAUGP

UUAACATJC

GUTUAACAU

UCCAAGU1J

UUCCAAGU

UUUtuUucc

CUGUGCAA

AACUGUGC

AACUUGUIJ

GAACUTUGU

UGUAUAAG

CUGUAUAA

CUCUGUAU

UCUCUGUA

CGUCUCUG

AUCCAAGU

AAUCCAAG

UAAAAUCC

CGCAGUAA

CCGCAGUA

UCCGCAGU

GUCCGCAG

CUGUUAU

UCUGUTUAU

UGUUCUGU

UAAUACUG

CUUGCUAA

UGCUUGCU

UUTGCUTUGC

UCCUTUAGU

GUGCUCCU

SCUGAUGA

TCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

*CUGAUGA

*CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAA AUAAAAGC GAA AUAUAAAA GAA ACCCAUUU GAA AACCCAUU GAA AAACCCAU GAA ACAUGAAA GAA AACAUGAA GAA AGUtJAACA GAA ACAGLTUUC GAA AGACAGUU GAA ACUGUGCA GAA AACUGUGC GAA ACUUGUUA GAA AACUUGUU GAA AGAACUtJG GAA AAGAACUU GAA AUAAGAAC GAA ACGUCUCU GAA AACGUCUC GAA AGUAACGU GAA AUCCAAGU GAA AAUCCAAG GAA AAAUCCAA GAA AAAAUCCA GAA ACUGUCCG GAA AACUGUCC GAA AUUAACUG GAA AGUGCAUU, GAA ACUGUAGU GAA AUACUGUA GAA AAUACUGU GAA AUGGCCAU GAA AGUGAUGG

GCUUUTUAUA

UUUUAUAUC

AAAUGGGUU

AAUGGGUUU

AUGGGUTUUC

UUUCAUGUU

UUCAUGUUA

UGUtJAACUU

GAAACUGUC

AACUGUCUU

UGCACAGLU

GCACAGUUA

UAACAAGtU

AACAAGUUC

CAAGUUCUU

AAGUUCUUA

GUUCUTUAUA

AGAGACGUU

GAGACGUTUA

ACGUUIACUU

ACUIJGGAIU

CUUGGAUUU

tJUGGAULTUUI

UGGAUUUTUA

CGGACAGUU

GGACAGUUA

CAGUTUAAUA

AAUGCACUA

ACUACAGUA

UACAGUAUU

ACAGUAUUA

AUGGCCAUC

CCAUCACUA

UCACAGAU

ACAGAUGU

UCAUGUULA

CAUGUUAA

AUGUUAAC

AACUUGGA

ACUULGGAA

GGAAAAAA

UUGCACAG

GCACAGUU

AACAAGUUI

ACAAGLTUC

CUUAUACA

UUAUACAG

AUACAGAG

UACAGAGA

CAGAGACG

ACUUGGAU

CUUGGAUU

GGAUUUTUA

UUACUGCG

UACUGCGG

.ACUGCGGA

CUGCGGAC

AAUAACAG

AUAACAGA

ACAGAACA

CAGUAUUA

UUAGCAAG

AGCAAGCA

GCAAGCAA

ACUAAGGA

AGGAGCAC

S S 55 5

S

S

AO

C

2096 2100 2104 2106 2107 2110 2112 2113 2118 10 2127 2128 2129 2140 2141 15 2150 2172 2174 2190 2193 2208 2209 2214 2221 2234 2238 2250 2257 2271 2278 2279 2287 2288 2289

GAGUGAU

LTLJAAGAG'

AAGAUIJA

GUAAGALTI

GGUAAGAI

GAUGGUA2 AUGAUGGt

CAUGAUGC

ACAUUCAL

UGCAGGG;

UtJGCAGGC

CUUGCAGG

GGUGCCUG

AGGUGCCU

UGCAGGCA

CCUGUGUA

CCCCUGUG

UUCUGGAG

UUCUUCUG

CUGAUTUGU

UCUGAUUG

UGAUCUCU

UGCUUCCU

GCAGGAGG

UUUICGCAG

UGAUCACU

CACUGUGU

GAACUGCU

AGUGGUGG

AAGUGGUG

ACAGUCUA

GACAGUCU

tJGACAGUC G CUGAUGA U CUGAUGA k. CUGAUGA J CUGAUGA J CUGAUGA k CUGAUGA J CUGAUGA

CUGAUGA

JCUGAUGA

CUGAUGA

CUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA I

CUGAUGA)

CUGAUGA)

CUGAUGA)

CUGAUGA Y CUGAUGA Y~ CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X X GAA AGUGCUCC X GAA AUGGAGUG X GAA AGUGAUGG X GAA AGAGUGAU X GAA AAGAGUGA X GAA AIJUAAGAG K GAA AGAUUAAG K GAA AAGAUUAA K GAA AUGGUAAG KGAA ACAUUCAU C GAA AACAUUCA C GAA AAACAUUC GAA AUCUUGCA GAA AAUCUUGC GAA AGGUGCCU GAP. ACAU-UCCU GAP. AUACAUUC GAA AUUUCUUC GAA AGGAUUUC GAP. AUUUCUUU GAP. APUUUCUrJ GAP. AUUGUAAU GAP. AUCUCUGA GAP. AUGGUGCU GAA AGGUAUGG GAP. AGGUUUCG GAP. AUCACUGA GAP. AUGGCCAC GAP. ACUGCUGA GAP. APCUGCUG GAP. AGUGGUGG GAP. AP.GUGGUG GAA AAP.GUGGU

GGAGCACUC

CACUCCAUC

CCAUCACUC

AUCACUCUu UCACUCUtJA

CUCUUAAUC

CUUAAUCUU

UUAP.UCUUA

CUUTACCAUC

AUGAP.UGUU

UGAAUGUUU

GAAUGUTUUC

UGCAAGAUUT

GCAAGAUtJC AGGCACCUA1

AGGAP.UGUA

GAP.UGUAUA

GAAGAAAUC

GAAAUCCUC

AAP.GAAAUU

I

AP.GA.AUIJAC

AUUACAAPUC jz UCAGAGAtJC P~ AGC-ACCP.uA c CCAUACCUC c CGAAACCUC A UCAGUGAUC

A

GUGGCCAUCA

UC-AGCP.Gtn

C

CAGC-AGUUCC

CCACCACU U CACCACUUU1

A

ACCACUEJUA G

CAUCACUC

ACUCUUAA

UtJAPUCU

AAUCUJAC

AUCUTUACC

LTUACCAUC

ACCP.UCAU

CCAUCAUG

AUGAAUGU

UCCCUGCA

CC CUG CAP.

CCUGCAAG

CAGGCACC

AGGCACCU

UGCCUGCA

JACACAGG

ACAGGGG

'UCCAGAA

:AGAAGAA

.CAP.UCAG

'AAUCAGA

~GAGAUCA

LGGAAGCA

:CUCCUGC

~UGCGAAA

.GUGAUCA

CACAGUG

GCAGUTLJC

CACCACU

.C CACU

AGACUGU

GACUGUC

~CUGUCA

2296 AUUAGCAU CUGAUGA X GAA ACAGUCUA

C.

C C C C

C.

C C

*CC.

*u C C

C

C

CC..

C C C. C

C

C

C

2302 2310 2320.

2325 2329 2333 2334 2335 10 2352 2370 2371 2373 2374 15 2375 2376 2399 2400 2401 20 2403 2412 2433 2435 2437 2465 2476 2477 2483 2487 2493 2494 2504* 2513

GACACCAU

GGCUCGGG

AGUGAUCU

AACCAAGU

ULJUAAACC

UGUUUtJUA

UTUGUUUUUE

GUJGUULU

UCUUGUUG

CCUAAAAU

UCCUAAAA

GGUCCUAA

UGGUCCUA

CUGGUCCU

CCUGGUCC

UUCAAUA

CtJUUCAAU

UCUUUJCAA

ACUCUULUC

UCUUCUGU

CAGUGAUA

UGCAGUGA

UUUGCAGU

UIJUCCACA

GUAUGCUG

GGUAUGCUC

CAGUGAGG C

UGAACAGU

GUULCCUJGC

GGUTUCCUC

ACUUGUCC C CCAGAUUA C CUGAUGA X GAA AGCAUGAC CUGAUGA X GAA ACACCAUUJ CUGAUGA X GAA AGGCUCGG CUGAUGA X GAA AUCUGAGG CUGAUGA X GAA AGUGAUCU CUGAUGA X GAA ACCAAGUG CUGAUGA X GAA AACCAAGU CUGAUGA X GAA AAACCAAG CUGAUGA X GAA AUTUUGUG CUGAUGA X GAA AUUCCAGG CUGAUGA X GAA AAUUCCAG CUGAUGA X GAA AUAAUUCC CUGAUGA X GAA AAUAAUUC CUGAUGA X GAA AAAUAAUU CUGAUGA X GAA AAAAUAAU CUGAUGA X GAA ACAGCGUG CUGAUGA X GAA AACAGCGU CtJGAUGA X GAA AAACAGCG CUGAUGA X GAA AUAAACAG CUGAUGA X GAA ACUCUUUC CUGAUGA X GAA ACACCtJUC CUGAUGA X GAA AGACACCU 7UGAUGA X GAA AUAGACAC UGAUGA X GAA AGCCCUUC :UGAUGA X GAA ACUIJUCCA 'UGAUGA X GAA AACUTUUCC UGAUGA X GAA AUG CUGAA .UGAUGA X GAA AGGUAUGC UTGAUGA X GAA ACAGUGAG UTGAUGA X GAA AACAGUGA UGAUGA X GAA AGGUUCCU ~UGAUGA X GAA ACUUGUCC UAGACUGUC

AUGCUAAU

GUCAUGCUA

AUGGUGUC

AAUGGUGUC

CCCGAGCC

CCGAGCCUC

AGAUCACU

CCUCAGAUC ACtJUGGUU AGAUCACUU

GGULJUAAA

CACUUGGUU

UAAAAACA

ACUUGGUUU

AAAAACAA

CUUGGUtJUA

AAAACAAC

CACAAAAUA CAACAAGA CCUGGAAUIJ AUUUUAGG CUGGAAUtJA

UUUUAGGA

GGAAUUAUU

UUAGGACC

GAAUUAUTJU

UAGGACCA

AAUUAUUUU

AGGACCAG

AUUAUUUUA

GGACCAGG

CACGCUGUU

UAUUGAAA

ACGCUGUUU

AUUGAAAG

CGCUGUTUUA

UUGAAAGA

CUGUTUUAUU

GAAAGAGU

GAAAGAGUC

ACAGAAGA

GAAGGUGUC

UAUCACUG

AGGUGUCUA

UCACUGCA

GUGUCUAUC

ACUGCAAA

GAAGGGCUC

UGUGGAAA

UGGAAAGUIJ

CAGCAUAC

GGAAAGUUC

AGCAUACC

UUCAGCAUA

CCUCACUG

GCAUACCUC

ACUGUUCA

CUCACUGUTU

CAAGGAAC

UCACUGUUC

AAGGA.ACC

AGGAACCUC

GGACAAGU

GGACAAGUC UAAUCUGG 9 2515 CUCCAGAU CTJGAUGA X GAA AGACUUGU ACAAGTJCUA AUCUGGAG a. a 0O a 0 0fe* 4S 0 0 C Sf~ 0 a 251 252 253 253 256 2 5 6.

256, 2565 10 2572 2574 2576 2577 2583 2586 2587 2589 2606 2608.

2609 2611 2612 2619 2630 2634 2636 2640 2641 2643 2661 2662 2665 2666 8 CAGCUCC 9 GUUAGAC 3 GCAUGU[ 5 GUGCAUC D CCAGAAC 2 AGCCAGA

IGGAGCCA

3AGGAGCC

GUUAAUA

AGGGUUTA

GGAGGGU

AGGAGGGI

CGGAUAAC

UUEJCGGAT

UUTUUCGGI

AUUUUCC

CAGAAGAP

UUCAGAAG

tUUUCAGAA

UAUUUCAG

UUAUUUCA

UCAGUCUU

UUGAUAGG

AUAAUUGA

UUAUAAIU

UCCAUUAU

GUCCAUUA

GGGUCCAU

UCCAAAGG

AUCCAAAG

CUCAUCCA

GCUCAUCC

3U CUGAUGA JA CUGAUGA ;U CUGAUGA ,A CUGAUGA A CUGAUGA .G CUGAUGA A CUGAUGA G CUGAUGA A. CUGAUGA U CUGAUGA J CUGAUGA

CUGAUGA

J CUGAUGA2

CUGAUGA

CUGAUGA x CUGAUGA X~ CUGAUGA x CUGAUGA X CUGAUGA

X

CUGAUGA X CUGAUGA x CUGAUGA x CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA

X

CUGAUGA

X

CUGAUGA X X G X GI X G.Z X GA X GA X GA XC GA K GA

SGA

CGAj

G,

GA)

GA

GA;

GA.2

GAPZ

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

kA AUCAGCUC

AGUGAUCA

kA AGAGUGAU A AGUCGCAG

~AGAGUCGC

LAGAGAGUC

AAAGAGAGU

AAGCCAGAA

AAGGAGCCA

AAUAGGAGC

AAAUAGGAG

1AGGGUUAA

~AGGAGGGU

~AAGGAGGG

~AUAAGGAG

SACCUUUUC

SAGACCTJU

AAGACCUU

AGAAGACC

AAGAAGAC

AURJJCAGA

AGUCAGUC

AGGUAGUC

AUAGGUAG

AUUGAUAG

AAUUGAUA

AUAAUUGA

ACUEJCAUC

AACUUCAU

AGGAACUU

AAGGAACU

CUGAUGA X GAA AUUAGACU AGUCUAAi

GAGCUGAI

UGAUCACI

AUCACUCI

CUGCGAL-t GCGACtJCL

GACUCUCL

ACUCUCUUJ

UUCUGGC U

UGGCUCCU

GCUCCUAIJ

CUCCUAUU,

UUAACCCUi ACCCUCCU71

CCCUCCUU)

CUCCUUAU(

GAAAAGGUC

AAAGGUCU.

AAGGUCUUC

GGUCtJUCuTrJ

GUCUUCUUC

UCUGAAAUA

GACUGACUA

GACUACCUA

CUACCUAUC

CUAUCAAUU

UAUCAATUA

UCAAUUAUA

GAUGAAGUU

AUGAAGUUC

AAGtJUCCUJ

AGUUCCUUIJ

LTC UGGAGCUG JC ACUCUAAC JC UAACAUGC JA ACAUGCAC JC UCUIJCUGG IC UUCUGGC U Vu CUGGCUCC rC UGGCUCCU C CUAUIJAAC A UUAACCCU U AACCCUCC A. ACCCUCCU 2CUUAUCCG J AUCCGAAA

UCCGAAAA

-CGAAAAAU

IUCULJCUG

JCUUCUGAA

*UUCUGAAA

CUGAAAUA

UGAAAUAA

AAGACUGA

CCUAUCAA

UCAAUJAU

AAUUAUAA

AUAAUGGA

UAAUGGAC

AUGGACCC

CCUTUUGGA

CUUUGGAU

UGGAUGAG

GGAUGAGC

2688 UCAUAAGG CUGAUGA X GA; a .1.

a.

a a a 2692 2693 2714 2715 2730 2731 2744 2748 10 2761 2762 2763 2775 2776 2783 2789 2790 2796 2797 2804 2809 2864 2872 2886 2892 2894 2904 2914 2925 2926 2962 2973 2976

GGCAUCAL

UGGCAUCP

CCCGGGCP

UCCCGGGC

CCCAGUUJ

GCCCAGUU

UUICCAAGU

ccucuucc

UUUUCCAA

CUUTUUCCA

ACUUUUCC

GAUGCUUG

UGAUGCUU

CAAAUGCU

UAAUG CCA UUAAUG CC

GAUUTUCUU

UGAUUUCU

ACGUAGGU

CCGGCACG

GAGCUULUG

AGUCAUCA

AAGAUUUUJ

UGGGUCAA

UGUGGGUC

UGGUGGCC

CACGUTJCA

AGCAGGUU

CAGCAGGU

CACCAUCA

UAUUCAAC

CAGUAUUC

I CUGAUGA

LCUGAUGA

,CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CTJGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA2 CUGAUGA2 CUGAUGA2

CUGAUGA

CUGAUGA

GAP

GAP

GAP

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GMA

GAA

GAA

GAA

GMA

GMA

GMA

GMA

GMA

GMA

GAA

GMA

GAA

GMA

GMA

GMA

GAA

GMA

GMA

GMA

GMA

GMA

AGCCGCUC

AGGGAGCC

MAGGGAGC

ACUCCCAC

ACUCCCA

AGUCUCUC

MAGUCUCU

AUUtJGCCC

AGUGALUU

AGCCCCUC

MAGCCCCU

AAAGCCCC

ACCACUUU

AACCACUU

AUG CtUGA

AUGCUGAU

MAUGCUGA

AUG C CA

MAUGCCAA

AUUTUCUUA

AGGUGAUU

ACUCGCUG

AGCUTJUGU

AGCUCAGU

AUTUUUUAG

AGAULTIUU

AUGUGGGU

AUGGUGGC

ACCACGUU

AACCACGU

AGGCCCUC

AUCACCAU

ACMAUCAC

GAGCGGCUC

GGCUCCCU

GCUCCCUUA

GUGGGAGUU

UGGGAGUU

GAGAGACU

AGAGACUUA

GGGCAAMUC

AMUCACUU

GAGGGGCUU

AGGGGCUUU

GGGGCUUUU

AAAGUGGUU

MGUGGUUC

UCAAGCAUC

AUCAGCAUU

UCAGCAUUU

UUJUGGCAUU

UUGGCAUUA.

UAAGAAAUC

MAUCACCUA

CAGCGAGUA

ACAAAGCUC

ACUGAGCUA

CUAMAAAUC1 AAAAAUCUtJ

ACCCACAUU

GCCACCAUC

MACGUGGU

ACGUGGI.TtA2

GAGGGCCUC

AUGGUGALU

GUGAUUTGUUC

CCUUTAUGA

AUGAUGCC

UGAUGCCA

UGCCCGGG

GCCCGGGA

MAACUGGG

MACUGGGC

ACUUGGAA

GGAAGAGG

UUGGAAAA

UGGAAAMG

GGAAAMGU

CAAGCAUC

AAGCAUCA

AGCAUUJUG

UGGCAUUA

GGCAUUJAA

AAGAAAUC

AGAAAUCA

P.CCUACGU

CGUGCC.GG

CAAAGCUC

LJGAUGACU

A~AAAUCUU

LUGACCCA

GACCCACA

GGCCACCA

JGMACGUG

kACCUGCU

%ICCUGCUG

JGAUGGUG

UTUGAAUA

MAUACUG

d. *fl.

2981 2990 2998 3000 3002 3008 3012 3029 3030 3032 3033 3034 3035 3036 15 3037 3039 3057 3070 3120 3124 3129 3146 3147 3155 3161 3162 3163 3172 3178 3189 3205 3206

AULJUGCAI

GAUUUtCCJ

GUUGGAGJ

UAGUtJGGj

GGUAGUUC

UCUUGAGC

TJUGCUCLTL

GAAAAAAI

AGAAAAA-Z

UGAGAAAP

UTUGAGAAP

GUJUGAGAP

UGUUGAGA

UUGUU!GAG

CUUGUUGA

UCCUTUGLU

UCCAUGtJG ucTurcu

ACGCUATJC

GGUGACGC

CUGCUGGU

AGCUCGCA

GAGCUCGC

GAAAGCCG

CUUCCtJGA

UCUUCCUG

AUCUUCCU

CAGACUU

AUCACUCA

ucuuccuc

ACCGUCAG

AACCGUCA

7CUGAUGA k. CUGAUGA k. CUGAUGA

~CUGAUGA

CUGAUGA

CUGAUGA

J CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

LCUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA)

CUGAUGA)

CUGAUGA)

CUGAUGA)

CUGAUGA Y.

CUGAUGA Y CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X

IGA-Z

GJ2U

GAP

GAl

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GA.,

GA-;

GA)

GAI

~AtUCAACA

~AUUUGCAG

~AUUTUCCAU

SAGAUUUCC

'AGAGAUJUU

~AGIJEGGAG

AGGUAGUU

AGUCACGU

AAGUCACG

AUAAGUCA

AAUAAGUC

AAAUAAGU

AAAAUAAG

AAAAAUAA

AAAAAAUA

AGAAAAAA

AGUGCUGC

AGGCUCCA

AGUCUUGG

AUCUAGUC

ACGCUAUC

AGCUUUCG

AAGCUUUC

AGCUCGCA

AGCCGGAG

AAGCCGGA

AAAGCCGG

AUCUUCCU

ACUUUUAU

ACATJCACU

AUCCUCCU

AAUCCUCC

UGUUGAAU

CUGCAAAUj

AUGGAAAU(

GGAAAUCUC

AAAUCUCUC

CUCCAACU;7

AACUACCUC

ACGUGACUL

CGUGACIJP

UGACUIJAUU

GACUUAUUU

ACUJUAUUU

CUUAUUTUUU

UUAUUUUUU

UALTUUULJUC

UULUTJUCtJC

GCAGCACUA

UGGAGCCUA

CCAAGACUA

GACUAGAUA

GAUAGCGUC

CGAAAGCUU

GAAAGCUUU

UGCGAGCUC

CUCCGGCUU

UCCGGCUUU

CCGGCUUUC

AGGAAGAUA

AUAAAAGUC

AGUGAUGUU

AGGAGGALU

GGAGGAUTUC

~CUGCAAAU

~UGGAAAUC

:UCUCCAAC

:UCCAACUA

CAACUACC

CCUCAAGA

AAGAGCAA

AUUIJUUUC

UEJuuUCU

UTJUUCUCA

UUUCUCAA

UTUCUCAAC

UCUCAACA

CUCAACAA

UCAACAAG

AACAAGGA

CACAUGGA

AGAAAGAA

GAUAGCGU

GCGUCACC

ACCAGCAG

UGCGAGCU

GCGAGCUC

CGGCUUUC

UCAGGAAG

CAGGAAGA

AGGAAGAU

AAAGUCUG

UGAGUGAU

GAGGAAGA

CUGACGGU

UGACGGUU

3214 CUUGUAGA CUGAUGA X GAA ACCGUCAG CUGACGGUU UCUACAAG 3215 3216 3218 3231 3235 3244 3249 3250 3251 3.253 3254 3259 3260 3261 3262 3284 3285 3290 3292 20 3293 3306 3307 3310 3333 3334 3336 3337 3338 3339 3341 3363 3364 3370

CCUTUGUAG

UCCUTUGUA

GCUCCUUIG

UCCAUAGU

AUCUUCCA

AGAAAUCA

CUGUAAGA

ACUGUAAG

AACUGUAA

AAAACUGU

GAAAACUG

CACUUGAA

CCACUTUGA

GCCACUUG

GGCCAC'TJU

AAGACAGG

GAAGACAG

UUCUGGAA

CUtJUCUGG

ACUUEJCUG

UCCCGAUG

GUCCCGAU

CAGGUCCC

GAUAAAAG

AGAUAAAA

UCAGAUAA

CUCAGAUA

UCUCAGAU

ULJCUCAGA

UGUUCUCA

AAAUCACA

AAAAUCAC

AAGGCCAA

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X GAA AACCGUCA GAA AAACCGUC GAA AGAAACCG GAA AUGGGCUC GAA AGUGAUGG GAA AUCUUCCA GAA AUCAGAUC GAA AAUCAGAU GAA AAAUCAGA GAA AGAAAUCA GAA AAGAAAUC GAA ACUGUAAG GAA AACUGUAA GAA AAACUGUA GAA AAAACUGU GAA ACUCCAUG GAA AACUCCAU GAA ACAGGAAC GAA AGACAGGA GAA AAGACAGG GAA AUGCACUU GAA AAUGCACU GAA AUGAAUGC GAA AUGUUUCU GAA AAUGUUUC GAA AGAAUGUU GAA AAGAAUGU GAA AAAGAAUG GAA AAAAGAAU GAA AUAAAAGA GAA AUCUUCAC GAA AAUCUUCA GAA AUCACAAA UGACGGUUU CUACAAGG GACGGUUUC UACAAGGA CGGUTUUCUA CAAGGAGC GAGCCCAUC ACUAUGGA CCAUCACUA UGGAAGAU UGGAAGAUC

UGAUUUCU

GAUCUGAUU UCUUACAG AUCUGAUUU CUUACAGU UCUGAUUJLC UUACAG-U UGAUUUCUU ACAGUUUU GAUUUCUUA CAGUUUUC CUUACAGUU UUCAAGUG UUACAGUUU UCAAGUGG UACAGUUUU CAAGUGGC ACAGUUUUC AAGUGGCC CAUGGAGUU CCUGUC-U AUGGAGUUC CUGUCUUC GTJUCCUGUC UUCCAGAA UCCUGUCUU CCAGAAAG CCUGUCUUC CAGAAAGU AAGUGCAUU CAUCGGGA AGUGCAUUC AUCGGGAC GCAUUCAUC GGGACCUG AGAAACAUU CUtJUUAUC GAAACAUUC UULJIUAUCU AACAUTUCUU UUTAUCUGA ACAtJUCUUU UAUCUGAG CAUTUCUUUU AUCUGAGA AUTUCUUUUA UCUGAGAA UCUUUUAUC UGAGAACA GUGAAGAUtJ UGUGAULTU UGAAGAUUU GUGAUULU UTUUGUGAUTU UUGGCCTU 3371 CAAGGCCA CUGAUGA X GAA AAUCACAA 9* 3372 3378 3388 3390 3391 3392 3394 3406 3407 3424 3427 3432 3433 3436 3451 3458 3460 3462 3464 3465 3474 3476 3500 3502 3503 3510 3512 3525 3527 3528 3530 GCAAGGCC CUGAUGA X GAA AAAUCACA UCCCGGGC CUGAUGA X GAA AGGCCAAA CUUAUAAA CUGAUGA X GAA AUCCCGGG UUCUUAUA CUGAUGA X GAA AUAUCCCG GUUCUUAU CUGAUGA X GAA AAUAUCCC GGUUCUUA CUGAUGA X GAA AAAUAUCC GGGGUUCU CUGAUGA X GAA AUAAAUAU UCUCACAU CUGAUGA X GAA AUCGGGGU UUCUCACA CUGAUGA X GAA AAUCGGGG AAGUCGAG CUGAUGA X GAA AUCUCCUU AGGAAGUC CUGAUGA X GAA AGUAUCUC UUCAGAGG CUGAUGA X GAA AGUCGAGU UUUCAGAG CUGAUGA X GAA AAGUCGAG CCAUUUCA CUGAUGA X GAA AGGAAGUC AGAIJUCGG CUGAUGA X GAA AGCCAUCC CAAAGAUA CUGAUGA X GAA AUUCGGGA GUCAAAGA CUGAUGA X GAA AGAUUCGG UUGUCAAA CUGAUGA X GAA AUAGAUUC UUUUGUCA CUGAUGA X GAA AGAUAGAU AUUUTUGUC CUGAUGA X GAA AAGAUAGA GUGCUGUA CUGAUGA X GAA AUUUUGUC UGGUGCUG CUGAUGA X GAA AGAUUUUG CUCCGUAA CUGAUGA X GAA ACCACACG UACUCCGU CUGAUGA X GAA AGACCACA AUACUCCG CUGAUGA X GAA AAGACCAC CACAGCAA CUGAUGA X GAA ACUCCGUA CCCACAGC CUGAUGA X GAA AUACUCCG AAGGAGAA CUGAUGA X GAA AUUUCCCA CUAAGGAG CUGAUGA X GAA AGAUUUCC CCUAAGGA CUGAUGA X GAA A'AGAUUUC CACCUAAG CUGAUGA X GAA AGAAGAUU UUEGUGAUUU UGGCCUUG UGUGAUUUU

GGCCUUGC

UUTUGGCCUU GCCCGGGA CCCGGGAUA UIJUAUAAG CGGGAUAUU UAUAAGAA GGGAUAUUtJ

AUAAGAAC

GGAUAUUUA

UAAGAACC

AUAUTUUAUA

AGAACCCC

ACCCCGAUU AUGUGAGA CCCCGAUUA

UGUGAGAA

AAGGAGAUA CUCGACUU GAGAUACUC

GACUUCCU

ACUCGACUU

CCUCUGAA

CUCGACUUC CUCUGAAA GACUUCCUC UGAAAUGG GGAUGGCUC

CCGAAUCU

UCCCGAAUC UAUCtJUUG CCGAAUCUA UCULUUGAC GAAUCUAUC UUTUGACAA AUCUAUCUU UGACAAAA UCUAUCUULU

GACAAAAU

GACAAAAUC UACAGCAC CAAAAUCUA CAGCACCA CGUGUGGUC

UUACGGAG

UGUGGUCUU

ACGGAGUA

GUGGUCUUA

CGGAGUAU

UACGGAGUA UUGCUGUG CGGAGUAUU GCUGUGGG UGGGAAAUC

UUCUCCUU

GGAAAUCtTU

CUCCUJUAG

GAAAUCUUC

UCCUUAGG

AAUCUUCUC CUUAGGUG CUUCUCCUU AGGUGGGU 3533 ACCCACCU CUGAUGA X GAA AGGAGAAG *6

C

3534 3542 3544 3548 3558 3575 3576 3577 3583 10 3613 3620 3623 3625 3628 3636 3638 3640 3645 3689 20 3690.

3699 3711 3718 3719 3723 3724 3735 3748 3755 3759 3765 3774

GACCCAC(

GGIUAUGGI

UGGGUAUC

CUCCUGGC

UCCAUUTUC

GACUGCAX

CGACUGCI

GCGACUGC

CCUCAGGC

GUACUCAG

GAGUAGAG

CAGGAGUA

UUCAGGAG

GAULTUCAG

AUCUGAUA

UGAUCUGA

CAUGAUCU

UCCAGCAU

GUUCUGCA

AGUUCUGC

UUtJUCCAC

AAAUCACC

UUGAAGCA

CUUGAAGC

UtJUGCUUG

AUIJUGCTU

UCCUGUG

GUAGUCUUJ

UUGGGAUG

UUGAUUGG

AUGGCALU

CCUGUCAG

CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA CUJGAUGA X GAA CUGAUGA X GAA

AGACCCAC

AUGGAGAC

ACUCCUGG

AGUCCUCA

AAGUCCUC

AAAGUCCU

ACUGCAAA

AGCUCUCA

ACUCAGGA

AGUACUCA

AGAGUACU

AGUAGAGU

AUUUCAGG

AGALTUUCA

AUAGAULTE

CUGAUGA X GAA AAGGAGAA CUGAUGA X GAA ACCCACCU IJUCUCCUUA GGUGGGUC AGGUGGGUC

UCCAUACC

GUGGGUCUC CAUACCCA GUCUCCAUA CCCAGGAG CCAGGAGUA CAAAUGGA UGAGGACUU UUGCAGUC GAGGACUUU

UGCAGUCG

AGGACIJUUU

GCAGUCGC

UUUGCAGUC GCCUGAGG UGAGAGCUC CUGAGUAC UCCUGAGUA CUCUACUC UGAGUACUC UACUCCUG AGUACUCUA CUCCUGAA ACUCUACUC CUGAAAUC CCUGAAAUC UAUCAGAU UGAAAUCUA UCAGAUCA AAAUCUAUC AGAUCAUG UAUCAGAUC AUG CUGGA GCCAAGAUU UGCAGAAC CCAAGAUUUI GCAGAACU GCAGAACUU GUGGAAAA GAAAAACUA GGUGAUJU UAGGUGAUU

UGCUEJCAA

AGGUGAUUU GCUUCAAG GAUEJtJGCUUJ CAAGCAAA ALTUUGCUUC AAGCAAAU GCAAAUGUA CAACAGGA AGGAUGGUA AAGACUAC UAAAGACUA

CAUCCCAA

GACUACAUC

CCAAUCAA

AUCCCAAUC AAUGCCAU AAUGCCAUA CUGACAGG CAGGAAAUA GUGGGUUU CUGAUGA X GAA AUCUGAUA CUGAUGA X GAA AUCUUGGC CUGAUGA X GAA AAUCUUGG CUGAUGA X GAA AGUUCUGC CUGAUGA X GAA AGUEJUUUC CUGAUGA X GAA AUCACCUA CUGAUGA X GAA AAUCACCU CUGAUGA X GAA AGCAAAUC CUGAUGA X GAA AAGCAAAU CUGAUGA X GAA ACAUUtJGC CUGAUGA X GAA ACCAUCCU CUGAUGA X GAA AGUCUUUA CUGAUGA X GAA AUGUAGUC CUGAUGA X GAA AUUGGGAU CUGAUGA X GAA AUGGCAUU 3787 AAACCCAC CUGAUGA X GAA AUUUCCUG .9 9 9* 9 9.

9. 9 9 3794 3795 3796 3800 3803 3808 3815 3816 3818 10 3827 3828 3830 3831 3841 3843 3844 3845 3850 3857 3858 3859 3862 3863 3872 3882 3887 3891 3898 3899 3900 3905 3906 3924

AGUAUGUA

GAGTJAUGU

UGAGUAUG

GAGUtJGAG

CAGGAGUU

GAAGGCAG

CCUCAGAG

UCCUCAGA

AGUCCUCA

CCUUGAAG

UCCUUGAA

UUUCCUUG

CUUCCLU

AGCUGAAA

GGAGCUGA

CGGAGCUG

UCGGAGCU

AAACLTUCG

CUGAAUTUA

CCUGAAUU

UCCUGAAU

GCUUCCUG

AGCUUCCU

CAUCAUCA

ACAUAUCU

CAUUUACA

AAAGCAUU C

GAACUUGAC

UGAACUTUGC

AUGAACUUC

GGCUCAUG C AGGCUCAU C AAGGUULUU C CUGAUGA X GAA ACCCACUA CUGAUGA X GAA AACCCACU CUGAUGA X GAA AAACCCAC CUGAUGA X GAA AUGUAAAC CUGAUGA X GAA AGUAUGUA CUGAUGA X GAA AGUUGAGU CUGAUGA X GAA AGGCAGG A CUGAUGA X GAA AAGGCAGG CUGAUGA X GAA AGAAGGCA CUGAUGA X GAA AGUCCUCA CUGAUGA X GAA AAGUCCUC CUGAUGA X GAA AGAAGUCC CUGAUGA X GAA AAGAAGUC CUGAUGA X GAA ACUUUCCU CUGAUGA X GAA AUACUUUTTC CUGAUGA X GAA AAUACUUU CUGAUGA X GAA AA.AUACUU CUGAUGA X GAA AGCUGAAA CUGAUGA X GAA ACUUCGGA CUGAUGA X GAA AACUUCGG CUGAUGA X GAA AAACUUCG CUGAUGA X GAA AUUAAACU 2tJGAUGA X GAA AAUUAAAC UGAUGA X GAA AGCUUCCU ZUGAUGA X GAA ACAUCAUC UGAUGA X GAA AUCUGACA UGAUTGA X GAA ACAUAUCU .UGAUGA X GAA AGCAUUUA .TUGAUGA X GAA AAGCAUUU TGAUGA X GAA AAAGCAUU UGAUGA X GAA ACUUGAAA UGAUGA X GAA AACUTUGAA UGAUGA X GAA AUUCtJUUC UAGUGGGUTU UACAUACU AGUGGGUUU ACAUACUC GUGGGUUUA CAUACUCA GUUUACAUA

CUCAACUC

UACAUACUC

AACUCCUG

ACUCAACUC CUGCCUUC UCCUGCCUU CUCUGAGG CCUGCCUtJC

UCUGAGGA

UGCCUUCUC UGAGGACU UGAGGACULJ CLUCAAGG GAGGACIJUC

UUCAAGGA

GGACUUCUU CAAGGAAA GACUEJCTUC

AAGGAAAG

AGGAAAGUA UUUCAGCU GAAAGUAUU

UCAGCUCC

AAAGUAUUU

CAGCUCCG

AAGUAUUUC AGCUCCGA UUTUCAGCUC CGAAGUUUT UCCGAAGUtJ UAAUUCAG CCGAAGUUJU AAUUCAGG CGAAGUUUA

AUUCAGGA

AGUUtJAAUU CAGGAAGC GUUUAAUUC AGGAAGCU AGGAAGCUC

UGAUGAUG

GAUGAUGUC AGAUAUGU UGUCAGAUA

UGUAAAUG

AGAUAUGUA AAUGCUUU UAAAUGCUU UCAAGLtUC AAAUGCUUU CAAGUUCA AAUGCUUUC AAGtJUCAU UUUCAAGUU

CAUGAGCC

UUCAAGUUC

AUGAGCCU

GAAAGAAUC AAAACCUU 3932 GUUCUUCA CUGAUGA X GAA AGGUUUUG 000000 0 o 0* ft 0** o o 00. 0000 o 0 00*.

0 00 0 0 000000 3933 3942 3943 3944 3945 3959 3965 3966 10 3974 3994 3998 4004 4006 15 4022 4023 4052 4056 4062 20 4067 4074 4081 4087 4094 4103 4110 4123 4124 4125 4132 4133 4149

AGUUCUUC

UUCGGUAA

AUUCGGUA

CAUUCGGU

GCALTUCGG

CAAACAUG

AGTJCAUCA

UAGUCAUC

CGCCCUGG

GGCCAACA

GAGAGGCC

GCAUGGGA

CAGCAUGG

UCCAGGUG

GUCCAGGU

UCUUGAGC

UCAAUCUU

CUCAAGUC

UUACUCUC

UUACUGGU

CUTLJACUUU

CGACUCCU

ACAGCCCC

UGACAUCA

GGCCUGCU

AUGGCAGA

AAUGGCAG

GAAUGGCA

AkCAGCUGG

CACAGCUG

CCUUCGCU

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X GAA AAGGUUUU GAA AGUUCUUC GAA AAGUUCUU GAA AAAGUUCU GAA AAAAGUUC GAA AGGUGGCA GAA ACAUGGAG GAA AACAUGGA GAA AGUCAUCA GAA AGUGCUGC GAA ACAGAGUG GAA AGGCCAAC GAA AGAGGCCA GAA AGCGCUTUC GAA AAGCGCUU GAA AGGCCUUG GAA AGCGAGGC GAA AUCUUGAG GAA AGUCAAUC GAA ACUCUCAA GAA ACUGGUUA GAA ACUUUUAC GAA ACUCCUUA GAA ACAGCCCC GAA ACAUCAGA GAA ACUGGGCC GAA AACUGGGC GAA AAACUGGG GAA AUGGCAGA GAA AAUGGCAG GAA ACGUGCCC CAAAACCUU UGAAGAAC AAAACCUUU GAAGAACU GAAGAACUU UUACCGAA AAGAACUUU UACCGAAU AGAACUUUU ACCGAAUG GAACUUUUA CCGAAUGC UGCCACCUC CAUGUUUG CUCCAUGUU UGAUGACU UCCAUGUUU GAUGACUA UGAUGACUA CCAGGGCG GCAGCACUC UGUUGGCC CACUCUGUU GGCCUCUC GUUGGCCUC UCCCAUGC UGGCCUCUC CCAUGCUG GAAGCGCUU CACCUGGA AAGCGCUUC ACCUGGAC CAAGGCCUC GCUCAAGA GCCUCGCUC AAGAtJUGA CUCAAGAUUL GACUtJGAG GAUUGACUU GAGAGUAA UUGAGAGUA ACCAGUAA UAACCAGUA AAAGUAAG GUAAAAGUA AGGAGUCG UAAGGAGUC GGGGCUGU GGGGCtJGUC UGAUGUCA UCUGAUGUC AGCAGGCC GGCCCAGUTU UCUGCCAU GCCCAGIJUU CUGCCAUU CCCAGUUIJC UGCCAUUC UCUGCCAUUT CCAGCUGU CUGCCAUUC CAGCUGUG GGGCACGUC AGCGAAGG GCGCAGGUU CACCUACG 4169 CGUAGGUG CUGAUGA X GAA ACCUGCGC -i 000000 000 0 0 0 3 3 4351 4355 4356 4357 4363 4364 4365 4367 4369 4370 4371 4389 4390 4391 4392 4398 4399 4400 4401 4402 4403 4404 4407 4413 4414 4415 4416 4417 4418 4419 4420 4421

UGUAAACT.

AAGGUGUZ

AAAGGUGI

UAAAGGUC

GAAAGAUP

GGAAAGAL

UGGAAAGP.

CAUGGAAA

CCCAUGGA

UCCCAUGG

CUCCCAUG

AUCACAAA

AAUCACAA

AAAUCACA

AAAAUCAC

AUIJAAAAA

UAUUAAAA

CUAUUAAA

ACUAUTUAA

CACUAUUA

GCACUAU

AGCACUAIJ

AAAAGCAC

AAAAAAAA

AAAAAAAA

CAAAAAAA

UCAAAAAA~

GUCAAAAA

AGUCAAAA

UAGUCAAA

UTJAGUCAA

GUUAGUCA

J CUGAUGA

CUGAUGA

J CUGAUGA

;CUGAUGA

LCUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA

CUGAUGA)

CUGAUGA)

CUGAUGA 2 CUGAUGA Y GAA AUAUAUGC GAA ACUUAUAU GAA AACUUAUA GAA AAACUUAU GAA AGGUGUAA GAA AAGGUGUA GAA AAAGGUGU GAA AUAAAGGU GAA AGAUAAAG GAA AAGAUAAA GAA AAAGAUAA GAA AGCAGCUG GAA AAGCAGCU GAA AAAGCAGC GAA AAAAGCAG GAA AUCACAAA GAA AAUCACAA GAA AAAUCACA GAA AAAAUCAC GAA AAAAAUCA GAA AAAAAAUC GAA AAAAAAAU GAA AUUAAAA1A GAA AGCACUAU GAA AAGCACUA GAA AAAGCACU GAA AAAAGCAC GAA AAAAAGCA GAA AAAAAAGC GAA AAAAAAAG GAA AAAAAAAA GAA AAAAAAAA

GCAUAUAU;

AUAUAAGT..

UAUAAGUUL

AUAAGUUP

UUACACCUL

UACACCUUU

ACACCUJUUA

ACCUUUAUC

CUUUAUCUU

UUUTAUCUUUJ

UJUAUCTJUUC

CAGCUGCUU

AGCUGCUUU

GCUGCUUUU

CUGCUUUUU

IJUUGUGAUU

UJTJGUGALTUU

UGUGALTJUU

GUGALUUU

UGATUUUUUJ

GAUUUUUUU

AUUUUUJUA

UUUUUAAUA

AUAGUGCUU

UAGUGCUUU

AGUGCIUUU

GUGCUUTUU

UGCUUUUU

GCUUUUULU

cLTUUUUUTU UUTUUUUUUu uuuuuIUUUu

SAGUUJUACA

J UACACCUU

JACACCUUU

CACCUUTUA

UAUCUUUC

IAUCUUJCC

UCUUUCCA

UUJUCCAUG

UCCAUGGG

CCAUGGGA

CAUGGGAG

UUUGUGAU

UTUGUGALU

UGUGAULU

GUGAULUU

UUUUUAAU

UUUAAUA

UTUUAAUAG

tJUAAUAGU

UAAUAGUG

AAUAGUGC

AUAGUGCU

GUGCUULUU

ULUUUUUU

UUUUUUUU

LTEUULUG

UUUUUGA

LUUUUGAC

ULTUUGACU

UUTUGACUA

UTUGACUAA

UGACUAAC

0 0 4422 UGUUAGUC CUGAUGA X GAA AAAAAAAA UtJUUUUUUU GACUAACA 4709 4712 4714 4723 4802 4803 4840 4852 4853 10 4854 4862 4863 4870 4878 4879 4881 4885 4886 4929 20 4930 4931 4932 4938 4939 4963 4965 4967 4968 4969 4970 4971 4978 4987

UGCUAGA

GCCUGCU

AGGCCUG(

ACAtJGUCI GCGUCUC2

UGCGUCUC

GCAUUGC.

GCCACUGI

AGCCACUC

AAGCCACL

GAGCUGGC

AGAGCUGCG

AAGGGUCA

AAAUGUAG

CAAAUGUA

CUCAAAUG

GGCCCUCA

GGGCCCUC

AUCCAGAA

AAUCCAGA

GAAUCCAG

AGAAUCCA

CCUCCCAG

GCCUCCCA

AAAAAAGA

CCAAAAAA

UtJCCAAAA

GUUCCAAA

AGUUCCAA

UAGUUCCA

UUAGUUCC

AUUUGC-U

AGGUCUAA

3CUGAUGA k. CUGAUGA

_CUGAUGA

I CUGAUGA k~ CUGAUGA

-CUGAUGA

JI CUGAUGA

SCUGAUGA

;CUGAUGA

T CUGAUGA

CUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA 2 CUGAUGA CUGAUGA Y~ CUGAUGA

Y

CUGAUGA

Y

CUGAUGA X K GAA ACUCCCGA K GAA AGGACUCC .K GAA AGAGGACU SGAA AGGCCUGC C GAA AUUCUUtJC C GAA AAUUJCUTJ I GAA AGCCCCGU GAA AtJGGCAUU GAA AAUGGCAU GAA AAAUGGCA GAA AGCCACUG GAA AAGCCACU GAA AGCUGGGA GAA AGGGUCAG GAA AAGGGUCA GAA AGAAGGGU GAA AUGUAGAA GAA AAUGUAGA GAA AUGUCCCC GAA AAUGUCCC GAA AAAUGUCC GAA AAAAUGUC GAA AUCCAGAA GAA AAUCCAGA GAA AUUUGUCC GAA AUAUUJGU GAA AGAUAUUU GAA AAGAUAUU1 GAA AAAGAUAU GAA AAAAGAUA GAA AAAAAGAU GAA AGUUCCAA GAA AUUUGCUU

UCGGGAGU(

GGAGUCCU(

AGUCCUCUI

GCAGGCCUI

GAAAGAA~n

AAAGAAUUL

ACGGGGCUC

AAUGCCAUL

AUG CCAULU

UGCCALTUUC

CAGUGGCUU

AGUGGCUUC

UCCCAGCUC

CUGACCCUU

UGACCCUUC

ACCCUUJCUA

UUCUACAUU

UCUACALTLJU

GGGGACAUU

GGGACAUUU

GGACAUJUUU

GACAUUU1JC

UUCUGGAUU

UCUGGAUUtC

GGACAAAUA

ACAAAUAUC

AAAUAUCUU

AAUAUCUUU

AUAUCUUUU

UAUCUUELJUtJ

AUCUUTU

UtJGGAACUA

AAGCAAAUU

CUCUAGCA

UAGCAGGC

k. GCAGGCCU

SAGACAUGU

JUGAGACGC

JGAGACGCA

AGCAAUGC

FUCAGUGGC

ICAGUGGCU

AGUGGCUU

CCCAGCUC

CCAGCUCU

UGACCCUU

CUACAUUU

UACAUUJUG

CAUUTUGAG

UGAGGGCC

GAGGGCCC

UUCUGGAU

UCUGGAUU

CUGGAUUC

UGGAUTUCU

CUGGGAGG

UGGGAGGC

UCUtUUUUTL

LUUULJUGG

UUUUGGAA

UTUUGGAAC

UUGGAACU

UGGAACUA

GGAACUAA

AAGCAAAU

UUAGACCU

498E 498S 499C 4996 4997 4998 5002 5013 5014 10 5016 5020 5024 5025 5027 5030 5031 5041 5042 5043 20 5047 5048 5051 5069 5074 5084 5087 5088 5089 5094 5097 5099 5102 AAGGUCUA CUGAUGA X GAA AAUUIJGCU AAAGGUCU CUGAUGA X GAA AAAUUUGC IUAAAGGUC CUGAUGA X GAA AAAAUUUG CAUAGGUA CUGAUGA X GAA AGGUCUAA CCAUAGGU CUGAUGA X GAA AAGGUCUA UCCAUAGG CUGAUGA X GAA AAAGGUCU CACUUCCA CUGAUGA X GAA AG.GUAAAG GGACAUAG CUGAUGA X GAA ACCACUUC UGGACAUA CUGAUGA X GAA AACCACTU AAUGGACA CUGAUGA X GAA AGAACCAC UGAGAAUG CUGAUGA X GAA ACAUAGAA CGAAUGAG CUGAUGA X GAA AUGGACAU ACGAAUGA CUGAUGA X GAA AAUGGACA CCACGAAU CUGAUGA X GAA AGAAUGGA AUGCCACG CUGAUGA X GAA AUGAGAAU CAUGCCAC CUGAUGA X GAA AAUGAGAA CAAAUCAA CUGAUGA X GAA ACAUGCCA ACAAAUCA CUGAUGA X GAA AACAUGCC UACAAAUC CUGAUGA X GAA AAACAUGC GUGCUACA CUGAUGA X GAA AUCAAAAC AGUGCUAC CUGAUGA X GAA AAUCAAAA CUCAGUGC CUGAUGA X GAA ACAAAUCA UCAGAGUU CUGAUGA X GAA AGUGCCAC UGGGCUCA CUGAUGA X GAA AGUtJGAGU GCCAAAAG CUGAUGA X GAA AUGGGCUC GGAGCCAA CUGAUGA X GAA AGUAUGGG AGGAGCCA CUGAUGA X GAA AAGUAUGG GAGGAGCC CUGAUGA X GAA AAAGUAUG UACUAGAG CUGAUGA X GAA AGCC.AAAA UCUUACUA CUGAUGA X GAA AGGAGCCA CAUCUUAC CUGAUGA X GAA AGAGGAGC GUGCAUCU CUGAUGA X GAA ACUAGAGG

AGCAAAUU

GCAAAUUU

CAAAUUUU

UUAGACCU

UAGACCUU

AGACCUUJ,

CUUUACCU

GAAGUGGUI

AAGUGGUUC

GUGGtJUCU)z

UUCUAUGUC

AUGUCCAUL

UGUCCAUuc

UCCAUUCUC

AUUCUCAUL

UUCUCAIJUC

UGGCAUGUU

GGCAUGUUU

GCAUGUUUU

GUUUUGAUU

UUUUGAUUU

UGAUUUGUA

GUGGCACUC

ACUCAACUC

GAG CC CAUA CCCAUACUtJ

CCAUACULU

CAUACUtUU

UUUUGGCUC

UGGCUCCUC

GCUCCUCUA

CCUCUAGUA

U UAGACCUtJ U AGACCUUU A GACCUTUUA U UACCUAUG UI ACCUAUGG PL CCUAUGGA k. UGGAAGUG J CUAUGUCC

-UAUGUCCA

k. UGUCCAUU

-CATJUCUCA

I CUCAUUCG

UCAUUCGU

AUUCGUGG

CGUGGCAU

GUGGCAUG

UUGAUUUG

UGAUT-tJGU

GAUUUGUA

UGUAGCAC

GUAGCACU

GCACUGAG

AACUCUGA

UGAGCCCA

CUUUGGC

UUGGCUCC

UGGCUCCU

GGCUCCUC

CUCUAGUA

UAGUAAGA

GUAAGAUG

AGAUGCAC

5119 CUCUGGCU CUGAUGA X GAA AGULUUCA UGAAAACUU AGCCAGAG 0* 5120 5129 5130 5134 5137 5139 5156 5157 5170 5175 5176 5178 5180 5181 15 5182 5187 5189 5190 5193 5195 5197 5200 5209 5210 5214 5218 5219 5220 5222 5226 5228 5229 5231

ACUCUGGC

GACAACCU

AGACAACC

CUGGAGAC

GGCCUGGA

AUGGCCUG

TJUCAGUGU

LUUCAGUG

UAGAAUGU

CAAAAUAG

CCAAAAUA

ACCCAAAA

AUACCCAA

AAUACCCA

UAAUACCC

UAUAUUAA

UAUAUATU

CUAUAUAU

GGACUAUA

CtJGGACUA

GUCUGGAC

AGUGUCUG

AUTUGAGUUJ

AAUTUGAGU

AAGAAAUU

UACCAAGA

AUACCAAG

AAUACCAA

AUAAUACC

CAGAAUAA

AACAGAAU

AAACAGAA

CAAAACAG

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X GAA AAGUUUUC GAA ACUCUGGC GAA AACUCUGG GAA ACCUAACU GAA ACAACCUA GAA AGACAACC GAA AGGCCAUC GAA AAGGCCAU GAA ACAUUUUC GAA AUGUGACA GAA AAUGUGAC GAA AGAAUGUG GAlA AUAGAAUG GAA AAUAGAAU GAA AAAUAGAA GAA ACCCAAAA GAA AUACCCAA GAA AAUACCCA GAA AUTUAAUAC GAA AUAUUAAU GAA AUAUAUUA GAA ACUAUAUA GAA AGUGUCUG GAA AAGUGUCU GAlA AGUTUAAGU GAA AUUGAGUU GAA AAUUGAGU GAA AAAUUGAG GAlA AGAAAUUG GAlA ACCAAGAA GAA AUACCAAG GAlA AAUACCAA GAlA AUAAUACC GAAAACUUA GCCAGAGU GCCAGAGUU AGGIJUGUC CCAGAGUUA GGUUGUCU AGUUAGGUU GUCUCCAG UAGGUUGUC UCCAGGCC GGUUGUCUC CAGGCCAU GAUGGCCUU ACACUGAA AUGGCCUUA CACUGAAA GAAAAUGUC ACAUUJCUA UGUCACAUt) CUAUUU-UG GUCACAUUC UAUUT-tJGG CACATUtCUA LTULTUtGGGU CAUUCUAUU UUGGGUAU AUUCUAULTU UGGGUAU7U UUCUALJUUU GGGUAUTUA UUUUGGGUA IJUAAtJAUA UUGGGUAUU AAUAUAUA UGGGUAUUA AUAUAUAG GUAUTUAAUA UAUAGUCC AUUAAUAUA UAGUCCAG UAAUAUAUA GUCCAGAC UAUAUAGUC CAGACACU CAGACACUU AACUCAAU AGACACUJA ACUCAAUU ACUUAACUC AAUUTUCUU AACUCAAUU UCUUGGUA ACUCAAUUU CUUGGUAU CUCAAUTUUC UTUGGUALU CAAUUUCUU GGUAUUAU UUCUUGGUA UUAUUCUG CUUGGUAUUJ AUEJCUGUU UUGGUAUUA UUCUGUUUJ GGUAUUAUU CUGUUUUG 5232 GCAAAACA CUGAUGA X GAA AAUAAUAC GAUAUUULJC GUAUUAUUC

UGUUUUGC

C

C

C

C.

C C

C

5236 5231 5238 5246 5247 5250 5284 5296 10 5297 5298 5299 5301 5305 5307 5336 5340 5345 5361 20 5363 5365 5367 5382 5383 5395 5417 5421 5426 5427 5428 5431 5432

CUGUGCA

ACUGUGC

AACUGUG

UCACAAC

UUCACAA'

UCUUUCA,

CUCCUCA(

AUGGAGAj UAUGGAG2

AUAUGGAC

GAUAUGGZ

UUGAUAUC

CGUUUUG7 CtJCGUJULt ACCtJUAUL

CUUGACCTJ

CuCCCu

GGUAUAGA

LUJGGUAUA

GGUUGGUA

UUGGUUGG

UGUUGGUG

GUGUUGGU

UGGGUCCC

ACGUGACU

GGAAACGU

GAAAAGGA

UGAAAAGG

AUGAAAAG

UAAAUGAA

UUAAAUGA

A CUGAUGA A CUGAUGA C CUGAUGA U CUGAUGA C CUGAUGA

-CUGAUGA

3 CUGAUGA

CUGAUGA

CUGAUGA

.CUGAUGA

k CUGAUGA

CUGAUGA

CUGAUGA

TCUGAUGA

FCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA 2 CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X X GAA ACAGAAUA X GAA AACAGAAU X GAA AAACAGAA X GAA ACUGUGCA K GAA AACUGUGC -K GAA ACUAACUG (GAA ACUGCAUU C GAA ACUCUCCU CGAA AACUCUCC rGAA

AAACUCUC

GAA AAAACUCU GAA AGAAAACU GAA AUGGAGAA GAA AUAUGGAG GAA ACCUUUUU GAA AUUGACCU GAA ACCUUAUU GAA ACGGGGUC GAA AGACGGGG GAA AGAGACGG GAA AUAGAGAC GAA AUUGGUUU GAA AAUUGGUU GAA ACUGUGUU GAA ACUUCCUG GAA ACUGACUU GAA ACGUGACU GAA AACGUGAC GAA AAACGUGA GAA AGGAAACG GAA AAGGAAAC

UAUUCUGU

AUUCUGUU

UTUCUGUUU

UGCACAGU

GCACAGUU,

CAGUUAGU1I AAUGCAGUc

AGGAGAGUI

GGAGAGUUI

GAGAGLUUL~

AGAGUUUUC

AGUUUUCUC

UUCUCCAU.P

CUCCAUAUC

AAAAAGGUC

AGGUCAAUA

AAUAAGGUC

GACCCCGUC

CCCCGUCUC

CCGUCUCUA

GUCUCUAUA

AAACCAATUU

AACCAAtIUC

AACACAGUU

CAGGAAGUC

AAGUCAGUC

AGUCACGUU

GUCACGLUU

UCACGUTUUC

CGUTUUCCUU

GLTUUCCUU

U UUGCACAG U UGCACAGU LU GCACAGUTJ LU AGUUGUGA k. GUUGUGAA J GUGAAAGA

-CUGAGGAG

J UUCUCCAU J UCUCCAUA J CUCCAUAU

UCCAUAUC

CAUAUCAA

LUCAAAACG

AAAACGAG

AAUAAGGU

.AGGUCAAG

AAGGGAAG

UCUAUACC

UAUACCAA

UACCAACC

CCAACCAA

CACCAACA

ACCAACAC

GGGACCCA

AGUCACGU

ACGUUUCC

UCCUUUTC

CCUUUUCA

CUUUUCAU

tJUCAUUUA

UCAUUAA

C

C

C

C C 5433 AUUAAAUG CUGAUGA X GAA AAAGGAAA UUUCCUiUU CAUUUAAU

C

C

C.

C

CC..

C.

C C

C.

C C

U

C

CC

C

*0 OC C

CC..

C

CC..

C

C

5434 5437 5438 5439 5448 5449 5454 5456 5458 10 *5464 5467 5489 5490 5501 15 5503 5504 5511 5512 55.13 20 5518 5521 5526 5537 5541 5544 5545 5546 5555 5557 5558 5559 5561

CAIJUAAAU

CCC CAUUA

UCCCCAUU

AUCCCCAU

GAUAGUGG

AGAUAGUG

GIJGUGAGA

UAGUGUGA

AIJUAGUGU

ULUCAGAU

UCCUUJCA

CGCCAGCU

GCGCCAGC

GUGCLTUAA

AAGUGCUU

AAAGUGCU

GGAGCL71A

AGGAGCUU

AAGGAGCU

UACUCAAG

LTUUUACUC

CACCUUUU

AAAUULACA

GCAUAAAU

CUUGCAUA

CCUUJGCAU

ACCUTUGCA

UGGAGAAA

ACUGGAGA

AACUGGAG

CAACUGGA

CCCAACUG

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

GAA AAAAGGAA GAA AUGAAAAG GAA AAUGAAAA GAA AAAUGAAA GAA AUCCCCAU GAA AAUCCCCA GAA AGUGGAAU GAA AUAGUGGA GAA AGAUAGUG GAA AGUGUGAG GAA AUUAGUGU GAA AUGCUCUUJ GAA AAUGCUCU GAA AUGCGCCA GAA AUAUGCGC GAA AAUAUGCG GAA AGUGCUTUA GAA AAGUGCUU GAA AAAGUGCU GAA AGCUtJAAA GAA AGGAGC-U GAA ACUCAAGG GAA ACCACCU GAA ACAUACCA GAA AUTUACAUA GAA AAUTUACAU GAA AAAUUACA GAA ACCUtJGCA GAA AUACCtJUG GAA AAUACCUU GAA AAAUACCU GAA AGAAAUAC

CUUUUCAUU

TUUUCAUUU

UUUCAUUUA

AUGGGGAUU

UGGGGAUUC

AUUCCACUA

UCCACUAUC

CACUAUCUC

CUCACACUA

ACACUAAUC

AAGAGCAUU1

AGAGCAUJA

UGGCGCAUA

GCGCAUAUUT

CGCAUAUJA

UAAGCACUU

AAGCACUU

AGCACUUUA

U!JUAAGCUC

AAGCUCCU

CCIJUGAGUA

AAGGUGGUA

UGGUAUGUA

UAUGUAAUU

AUGUAALUU

UGUAAUTUUA

UGCAAGGUA

CAAGGUAUTJi

AAGGUAUUUT

AGGUAUULUC

GUAUUUCUC

UAAUGGGG

AAUGGGGA

AUGGGGAU

CC.ACUAUC

CACUAUCU

UCUCACAC

UCACACUA

ACACUAAU

AUCUGAAA

UGAAAGGA

AGCUGGCG

GCUGGCGC

UUAAGCAC

AAGCACUU

AGCACUUU

UAAGCUCC

AAGCUCCU

AGCUCCUU

CULJGAGUA

GAGUAAAA

AAAAGGUG

UGUAAUU

AUtJUAUGC

UAUGCAAG

AUG CAAGG

UGCAAGGU

UtJUCUCCA

UCUCCAGU

CUCCAGLU

UCCAGUUG

CAGUUGGG

UUCCUUTUUC AULTUAAUG 5566 UGAGUCCC CUGAUGA X GAA ACUGGAGA UCCGUGGAtA UCUCCAGUU GGGACUCA 5573 AAUAUCCU CUGAUGA X GA7 0** 0 0 0 .00.

5579 5581 5582 5585 5586 5596 5600 5615 10 5616 5617 5618 5626 5627 5634 5644 5661 5674 5688 5691 5693 5694 5700 5702 5708 5719 5724 5728 5737 5741 5742 5749 UTUAACUA7

CAUUIAACL

UCAUTAAC

GGCUCALJL

UGGCUCATJ

CIJUCUAGU

UUTUCuTuc CAGUtJGAA

GCAGUEJGA

AGCAGUUG

AAGCAGUU

AAGUTUUCA

CAAGUUUC

CCCCAGGC

CAUGCUCA

UGUCUCCC

cccUUUc

CUGAAGAG

ACCCUGAA

AGACCCUG

UAGACCCU

GAUCUUUA

UUGAUCUU

GCCCACUU

AGCGAUCC

AGCUTUAGC

AGCCAGCU

AUCAAACA

UAGCAUCA

AUAGCAUC

UGCAUAAA

iCUGAUGA

JCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CtJGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAI

-GAP~

*GAP

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

AGUCCCAA

AUCCUGAG

AUAUCCUG

AAUAUCCU

ACUAAUAU

AACUAAUA

AUGGCUCA

*AGUGAUGG

*AUGGGCUU

AAUGGGCU

AAAUGGGC

AAAAUGGG

AGCAGUUG

AAGCAGUU

AGUU!JCAA

ACCCCAGG

ALJUCCCAU

ACCCUGUC

AGGCGCCC

AGUAGGCG

AGAGUAGG

AAGAGUAG

ACCCUGAA

AGACCCUG

AUCUUUAG

AGGCCCAC

AUCCAAGG

AGCGAUCC

AGCCAGCU

ACAGAGCC

AACAGAGC

AGCAUCAA

UUGGGACU(

CUCAGGAUI

CAGGAUAU.

AGGAUAUIJP

AUAUUAGUL

UAUUAGUUP

UGAGCCAUC

CCAUCACUPA

AAGCCCAUU

AGCCCAUUU

GCCCAUEU

CCCAUUUUC

CAACUGCUU

AACUGCUUU

UUGAAACUU

CCUGGGGUC

AUGGGAAUA

GACAGGGUA

GGGCGCCUA

CGCCUACUC

CCUACUCUU

CUACUCUUC

UtJCAGGGUC

CAGGGUCUA

CUAAAGAUC

GUGGGCCUU

CCtJUGGAUC

GGAUCGCUA

AGCUGGCUC

GGCUCUGUU

GCUCUGUJU

UUGAUGCUA

AGGAUAUU

UUAGUUAA

J AGUUAAUG

GUTJAAUGA

J AAUGAGCC

AUGAGCCA

ACUAGAAG

,GAAGAAAA

UUCAACUG

UCAACUGC

CAACUGCU

AACUGCUU

UGAAACUU

GAAACUUG

GCCUGGGG

UGAGCAUG

GGGAGACA

GGAAAGGG

CUCUUCAG

UUCAGGGU

CAGGGUCU

AGGGUCUA

UAAAGAUC

AAGAUCAA

AAGUGGGC

GGAUCGCU

GCUAAGCU

AGCUGGCU

UGUTUUGAU

UGAUGCUA

GAUGCUAU

UUUAUGCA

5751 CUUGCAUA CUGAUGA X GAA AUAGCAUC

GUCAUUUCA

GAUGCUALTIJ UAUGCAAG

C

C C. C 5752 5753 5761 5762 5767 5769 5773 5775 5776 10 5777 5788 5791 5793 5794 15 5800 5802 5808 5819 5824 5828 5837 5841 5842 5849 5851 5852 5853 5861 5862 5867 5869 5873 5875

ACUTUGCAU

AACUUGCA

UAGACCCU

AUAGACCC

AAUACAUA

UAAAUACA

AUCCUAAA

GCAUCCUA

CGCAUCCJ

GCGCAUCC

CUGAAGAG

ACCCUGAA

AGACCCUG

UAGACCCU

GAUCUUUA

UTUGAUCU

GCCCACUU

AGCGAUCC

AGCUUAGC

AGCCAGCU

AUCAAACA

UAGCAUCA

AUAGCAUC

UGCAUAAA

CUUGCAUA

ACUtJGCAU

AACUUGCA

UAGACCCU

AUAGACCC

AAUACAUA

UAAAUACA

AUCCUAAA

ACAUCCUA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA:

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GA-Z

GAA

GAA

GAA

GAA

GAA

AAUAGCAU

AAAUAGCA

ACUUGCAU

AACUUGCA

ACCCUAAC

AGACCCUA

ACAUAGAC

AUACAUAG

AAUACAUA

AAAUACAU

AGGCGCAU

AGUAGGCG

AGAGUAGG

AAGAGUAG

ACCCUGAA

AGACCCUG

AUCUUUAG

AGGCCCAC

AUCCAAGG

AGCGAUCC

AGCCAGCU

ACAGAGCC

AACAGAGC

AGCAUCAA

AUAGCAUC

AAUAGCAU

AAAUAGCA

ACUUGCAU

AACUUGCA

ACCCUAAC

AGACCCUA

ACAUAGAC

AUACAUAG

UGCUAUTUUA

AUG CAAGUTU

UGCAAGUUA

GUUAGGGUC

UAGGGUCUA

GUCUAUGUA

CUAUGUAUU

UAUGUAUUUJT

AUGUAUUUA

AUGCGCCUA

CGCCUACUC

CCUACUCUU

CUACUCUUC

UUCAGGGUC

CAGGGUCUA

CUAAAGAUC

GUGGGCCUU

CCUUGGAUC

GGAUCGCUA

AGCUGGCUC

GGCUCUGUU

GCUCUGUUU

UTUGAUGCUA

GAUGCUALU

AUG CUAUUU

UGCUALTUUA

AUGCAAGLU

UGCAAGUUA

GUUAGGGUC

UAGGGUCUA

GUCUAUGUA

CUAUGUAUU

AUG CUAUUU AUGCAAGU

*UGCAAGUU

AGGGUCUA

GGGUCUAU

UAUGUALU

UGUAUUUA

UUUAGGAU

UAGGAUGC

AGGAUGCG

GGAUGCGC

CUCUUCAG

IJUCAGGGU

CAGGGUCU

AGGGUCUA

UAAAGAUC

AAGAUCAA

AAGUGGGC

GGAUCGCU

GCUAAGCU

AGCUGGCU

UGUUTUGAU

UGAUGCUA

GAUGCUAU

UUUAUGCA

UAUGCAAG

AUGCAAGU

UGCAAGLU

AGGGUCUA

GGGUCUAU

UAUGUAUU

UGUAUUUJTA

UtJUAGGAU

UAGGAUGU

5876 GACAUCCU CUGAUGA X GAA AAUACAUA UAGUUAGtGC UAUGUAUUU AGGAUGUC 5877 5884 5892 5893 5904 5930 5937 5938 10 5940 5953 5958 5959 5962 15 5963 5964 5965 5967 5973 5976 5977 5978 5984 5996 5998 6002 6015 6021 6025 6026 6028 6029

AGACAUC(

AAGGUGCj

GGCUGCAC

UGGCUGCI

CAGCUUCT.

GAAGCAGC

UCCCCAAC

CUCCCCAP

uuCcc

AGGAAGCP

AUAAAAGG

GAUAAAAG

AUGGAUAA

CAUGGAUA

ACAUGGAU

UACAUGGA

AUTUACAUG

AGUUAAAU

UACAGUUA

CUACAGLU

UCUACAGU

UCAGGUTUC

GtJUACUTUA

CGGUTUACU

UCUUCGGU

CAGAGGCA

UAAGAACA

CACAUAAG

GCACAUAA

UGGCACAU

GUGGCACA

CUGAUGA

~CUGAUGA

3CUGAUGA k CUGAUGA

JCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA 2 CUGAUGA Y X GAA AAAUACAU X GAA ACAUCCUA K GAA AGGUGCAG K GAA AAGGUGCA KGAA ACUGGCUG GAA AUCCACUG C GAA AGCAGCAA IGAA AAGCAGCA [GAA AGAAGCAG 'GAA ACUCUUCU GAA AGCAUACU GAA AAGCAUAC GAA AGGAAGCA GAA AAGGAAGC GAA AAAGGAAG GAA AAAAGGAA GAA AUAAAAGG GAA ACAUGGAU GAA AUUACAUG GAA AAUUACAU GAA AAAUTUACA GAA ACAGUUAA GAA AGCUCAGG GAA AGAGCUCA GAA ACtJUAGAG GAA ACAUUCUU GAA AGGCAUAC GAA ACAGAGGC GAA AACAGAGG GAA AGAACAGA GAA AAGAACAG

AUGUAUUU,

UAGGAUGU

CUGCACCU

UGCACCJU(

CAGCCAGU(

CAGUGGAMt

UUGCUGCM.

UGCUGCUTUC

CUGCUJCtJL

AGAAGAGUI

AGUAUGCULt

GUAUGCUTUC

UGCUUCCUU

GCUTUCCUUU

CUUCCULUUu

LUJCCUUTUUA

CCUUUTUAUC

AUCCAUGUA

CAUGUAALU

AUGUAALUU

UGUAAUTUUA

UtJAACUGUA

CCUGAGCUC

UGAGCUCUA

CUCUAAGUA

AAGAAUGUA

GUAUGCCUC

GCCUCUGUJ

CCUCUGUUC

UCUGUUCUU

CUGUUCUUA

A~ GGAUGUCU

-UGCACCUJ

J CUGCAGCC

UGCAGCCA

:AGAAGCUG

J GCUGCtTUC J CtJUGGGGA

UUGGGGAG

J GGGGAGAA iUGCUUCCU

TCCUUUUAU

CUULTUATJC

UUAUCCAU

UAUCCAUG

AUCCAUGU

UCCAUGUA

CAUGUAAU

AUUTJAACU

UAACUGUA

AACUGUAG

ACUGUAGA

GAACCUGA

UAAGUAAC

AGUAACCG

ACCGAAGA

UGCCUCUG

UGUUCIJUA

CIJUAUGUG

UEJAUGUGC

AUGUGCCA

UGUGCCAC

6040 UAAACAAG CUGAUGA X GAA AUGUGGCA UGCCACAUC CUUGUUUA 6043 CUUUAAAC CUGAUGA X GAA AGGAUGUG CCUCUGUAA CACAUCCUU GUUUAAAG 6046 6047 6048 6055 6057 6061 6079 6082 6090 6091 6095 6104 6111 15 6124 6125 6126 6137 6i4l 6166 6169 6171 6181 6183 6187 6204 6226 6228 6229 6232 6235 6236 6239

AGCCUUUI

GAGCCUUL

AGAGCCUL

CAUACAGP

LUUCAUAC.P

UcCUcUUIP

GUGCUGA)

AAUGUGCU

CACUAGGG

UCACUAGG

AGGCUCAC

GGAGCCAG

GCUGCCAG

UUCCACAA

CUTUCCACA

UCUUCCAC

UGGCUAGU

CUUCtJGGC

GUGGAGAG

UUGGUGGA

UCUUGGUG

UGGAUUJA

UUUGGAUU

UUUGUUUG

UCUGGCUC

ACAACAAA

GAACAACA

GGAACAAC

AGAGGAAC

AGAAGAGG

AAGAAGAG

GUAAAGAA

SCUGAUGA

JCUGAUGA

JCUGAUGA

LCUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA 3 GAA ACAAGGAU GAA AACAAGGA GAA AAACAAGG GAA AGCCUUUA *GAA AGAGCCUU *GAA ACAGAGAG GAA ACGGUCCC GAA AUGACGGU GAA AUGUGCUG GAA AAUGUGCU GAA AGGGAAUG GAA AGGCUCAC GAA AGCCAGUA GAA AGCCGCUG GAA AAGCCGCU GAA AAAGCCGC GAA AGUCUUCC GAA AGUGAGUC GAA ACUGUCCC GAA AGGACUGU GAA AGAGGACU GAA AUCUtJGGU GAA AGAUCUUG GAA AtUUJAGAU GAA AGCCUGCU GAA AUUUGUCC GAA AGAUUUGU GAA AAGAUUUG GAA ACAAAGAU GAA ACAACAAA GAA AACAACAA GAA AGGAACAA

AUCCUUGU.

UCCUUGUUL

CCUUGUUUXP

UAAAGGCUC

AAGGCUCUC

CUCUCUGUA

GGGACCGUC

ACCGUCAUC

CAGCACAUU

AGCACAUUC

CAUUCCCUA

GUGAGCCUA

UACUGGCUC

CAGCGGCUU

AGCGGCUUU

GCGGCUUUU

GGAAGACUC

GACUCACUA

GGGACAGUC

ACAGUCCUC

AGUCCUCUC

ACCAAGAUC

CAAGAUCUA

AUCUAAAUC

AGCAGGCUA

GGACAAAUC

ACAAAUCUU

CAAAUCUUUTI

AUCUUUGUU

UUUGU7UGUU

UUGUUGUUC

UUGUUCCUC

JUAAAGGCU

JAAAGGCUC

AAGGCUCU

UCUGUAUG

UGUAUGAA

*UGAAGAGA

*AUCAGCAC

AGCACAUU

CCCUAGUG

CCUAGUGA

GUGAGCCU

CUGGCUCC

CUGGCAGC

UUJGUGGAA

UGUGGAAG

GUGGAAGA

ACUAGCCA

GCCAGAAG

CUCUCCAC

UCCACCAA

CACCAAGA

UAAAUCCA

AAUCCAAA

CAAACAAA

GAG CCAGA

UUUGUUGU

UGTUGUTUC

GU7UGLTICC

GUUCCUCU

CCUCTJUCU

CUCUTUCUU

UUCUUUAC

6241 6242 6244 6245 6246 6252 6280 6281.

6282 6283 6285 6289 6294 .6308 15 6309 6314 6331 6335 6339 6340 6342 6344 6347 6348 6349 6350 6351 6352 6353 6354 6355 6356 6357

GUGUAAA(

UGUGUAA)

UAUGUGtfl

GUAUGUGI

CGIJAUGUC

GULUGCC

AUUUAUAP

GAUUUtAUP

UGAULUAU

CUGAUUUA

ACCUGAUU

AGUULACCU

CtJUCCAGU

CUGAGUUU

UCUGAGUU

UUUTULJCU

AAUTUGACU

AGAGAAUU

AAGUAGAG

AAAGUAGA

AAAAAGUA

AAAAAAAG

AAAAAAAA

AAAAAAAA

AAAAAAAA

AAAAAAAA

AAAAAAAA

AAAAAAAA

AAAAAAAA

GAAAAAAA

GGAAAAAA

UGGAAAAA

ULTGGAAAA

3CUGAUGA k. CUGAUGA k CUGAUGA J CUGAUGA

;CUGAUGA

;CUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGAI

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA2 CUGAUGA CUGAUGA CUGAUGA CUGAUGA CUGAUGA CGAA AGAGGAAC C GAA AAGAGGAA CGAA AGAAGAGG GAA AAGAAGAG GAA AAAGAAGA GAA AUGUGUAA GAA AUUGCCAG GAA AAUTUGCCA GAA AAAUUGCC GAA AAAAUUGC GAA AUAAAALU GAA AUUUAUAA GAA ACCUGAUUL GAA ACCUCCUUJ GAA AACCUCCU GAA AGUUUAAC GAA AGGUCUUC GAA ACUGAGGU GAA AUUGACUG GAA AAUUGACU GAA AGAAUUGA GAA AGAGAAUU GAA AGUAGAGA GAA AAGUAGAG GAA AAAGUAGA GAA AAAAGUAG GAA AAAAAGUA GAA AAAAAAGU GAA AAAAAAAG GAA AAAAAAAA GAA AAAAAAAA GAA AAAAAAAA GAA AAAAAAAA

LTUCCUCUUC

CCUCUUCU.

CUCUTICUMt UCcttucuu

UUACACAUP

CUGGCAAUL

UGGCAAUUU

GGCAAUTUUU

GCAAUULTUA

AAUUUUAUA

UUAUAAAUC

AAUCAGGUA

AAGGAGGUU

AGGAGGUUA

GUUAAACUC

GAAGACCUC

ACCUCAGUC

CAGUCAAUU

AGUCAAtJUC

UCAAUUCUC

AAUUCUCUA

UCUCUACUU

CUCUACUUU

UCUACUUU

CUACUUUUU

UACUUUULTI

ACUUUTUTJU

CUUUUUUUU

uruuLUUUUu

UUUUUULUU

UUUUuuuuu

ULUUUUUUU

-UUUACACA

JUACACAUA

T ACACAuAc

LCACAUACG

LCGCAAACC

fUUAUAAAU

IUAUAAAUC

AUAAAUCA

UAAAUCAG

AAUCAGGU

AGGUAACU

ACUGGAAG

AAACUCAG

AACUCAGA

AGAAAAAA

AGUCAAUU

AAUUCUCU

CUCUACUUJ

UCUACUUU

UACLUUEJU

CUULUUUU

tUUUUUUU

ULTUUUUUU

uuuuEuuuu UTUuUUU

UUUUULUU

UUUUULTUU

UUUUULUU

UUUUUUUC

LUUUUUJCC

UUUTUUCCA

UUTUJCCAA

GUUCCUCUU CUUUACAC 6358 6359 6360 6361.

6362 6368 6373 6376 6388 6394 6401 6408 6409 6415 15 6416 6421 6423 6427 6428 6429 6433 6436 6437 6440 6441 6443 6444 6447 6450 6451 6461 6464 6468

UUUGGAIL

AUUUGGA.4

GAUUGG

UGAUUUG(

CUGAUUUCU

UAUTUAUCT

UGGGCUAI

UGCUGGGC

GUTJAUCAC

UUALUUUGL

UAAGGUUL

GAACAGCL

UGAACAGC

AAGACAUG

CAAGACAU

GAAAUCAA

UUGAAAUC

AUUAUTUGA

AAUtJAUEJG

UAAUUAUU

GAAUUAAU

UAAGAAUU

UUAAGAAU

UGAUUAAG

AUGAUUAA

UAAUGAUUT

UtJAAUGAU

CUCUUAAU

GGUCUCUTJ

UGGUCUCU

GUAUUUAU

GGAGUAUtJ

AAAAGGAG

k. CUGAUGA k. CUGAUGA

CUGAUGA

3 CUGAUGA

CUGAUGA

J CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

JCUGAUGA

TCUGAUGA

FCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA2

CUGAUGA

CUGAUGA)

CUGAUGA

CUGAUGA )o CUGAUGA Y CUGAUGA Y K GAA AA.AAAAAA ,K GAA AAAAAAAA GAA AAAAAAAA C GAA AAAAAAAA CGAA AAAAAAAA C GAA AUUUGGAA C GAA AUCUGAUU GAA AUUIAUCUG GAA AtJUUGCIJG GAA AUCACUAU GAA AUEJUGUUA GAA AGGUUUIJA GAA AAGOUUUU GAA ACAGCUAA GAA AACAGCUA GAA ACAUGAAC GAA AGACAUGA GAA AUCAAGAC GAA AAUCAAGA GAA AAAUCAAG GAA AU1JGAAAU GAA AUUJAUUGA GAA AAUUAUUG GAA AUtJAAUUA GAA AAUUIAAUU GAA AGAAUUAA GAA AAGAAUUA GAA AUUAAGAA GAA AUGAUUAA GAA AAUGAUUA GAA AUGGUCUC GAA AUUAUGGU GAA ATJAUrJA uuuuuumjj UuUUUUULTL

UUUUUUUTL

uuuuuurujt

UUCCAAAUC

AAUCAGAUP

CAGAUAAUA

CAGCAAAUA

AUAGUGAUA

UAACAAAUA

UAAAACCLtU AAAACCUtJA

UUAGCUGUU

UAGCUGUUC

GUUCAUGUC

UCAUGUCUU

GUCUUGALU

UCUUGAUUtJ

CTJUGAUUUC

AUIJUCAAUA

UCAAUAAUU1 CAAUAAUtJA

UAAUUAAUU

AAtTUAAUUC

UTUAAUUCIU

UAAUUCUUA

UTUCUUtAAUC

UUAAUCAUTJ

UAAUCAUUTA

GAGACCAUA

ACCAUAAUA

UAAUAAAUA

J UUUCCAAA JUTrJCCAAAU

IUCCAAAUC

J CCAAAUCA 7 CAAAUCAG

AGAUAAUA

LAUAGCCCA

IGCCCAGCA

GUGAUAAC

ACAAAUAA~

AAACCUUA

AGCUGUUC

GCUGUUCA

CAUGUCLJU

AUGUCUUJG

UUGAUUUC

GAUEJUCAA

UCAAUAAU

CAAUAATU

AAUAAUUA

AUUAATTJC

AAUTUCUTUA

AUUTCUUAA

CUUAAUCA

UIJAAUCAU

AAUCAUUA

AUCAUUAA

AUUAAGAG

AAGAGACC

AGAGACCA

AUAAAUAC

AAUACUCC

CUCCUUUU

6471 6474 6475 6476 6477 6497 6498 6503 6506 6507 6510 6515 6518 6519 6525 6530 6531 6534 6539 6547 6551 6S55 6559 6570 6571 6575 6582 6584 6585 6590 6609 6612 6615

UUGAAAAG

CUCUUGAA

UCUCUUGA

UUCUCUUG

UUUcUcUu

ACAAUCU

AACAAUUC

UGAGUAAC

AGCUGAGU

GAG CUGAG

AAGGAGCU

GUtJUGAAG

UGAGULTUG

CUGAGUUJ

ACAAACCU

AUCCUACA

UAIUGCUAC

AUGUAUGC

GACUCAUG

GAUGGAUG

GACUGAUG

CUtJUGACU(

CAULJCUUUC

CCAGAUGG C UCCAGAUG C CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA x CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X :UGAUGA X :UGAUGA X :UGAUGA X UGAUGA X UGAUGA X UGAUGA X GAA AUGGUUUU GAA AAUGGUUU GAA AUUCUAAU GAA ACAAUUCU GAA AACAAUTUC GAA AGUAACAA GAA AGCUGAGU GAA AGGAGCUG GAA AAGGAGCU GAA AGUUUGAA GAA ACCUGAGU GAA AACCUGAG GAA ACAAACCU GAA AUG CUACA GAA ACUCAUGU GAA AUGGACUC GAA AUGGAUGG GAA ACUGAUGG GAA ACCAUUCU GAA AACCAUUC CUGAUGA X GAA AGUAUUUA CUGAUGA X GAA AGGAGUAU CUGAUGA X GAA AAGGAGUA CUGAUGA X GAA AAAGGAGU CUGAUGA X GAA AAAAGGAG UAAAUACUC

CUUUUCAA*

AUACUCCUU UUCAAGAG UACUCCUUtj

UCAAGAGA

ACUCCUUULJ

CAAGAGAA

CUCCUUUUC

AAGAGAAA.

AAAACCAtnj AGAAUtJGU AAACCAUtJA

GAAIJUGUU

AUUAGAAUU GtJUACUCA AGAAUUGUU

ACUCAGCU

GAAUUGUUA

CUCAGCUC

UUGUtJACUC

AGCUCCUU

ACUCAGCUC

CUUCAAAC

CAGCUCCUU

CAAACUCA

AGCUCCIJUC

AAACUCAG

UUCAAACUC

AGGUUUGU

ACUCAGGUU

UGUAGCAU

CUCAGGUUU

GUAGCAUA

AGGUUUGUA

GCAUACAU

UGUAGCAUA

CAUGAGUC

ACAUGAGUC

CAUCCAUC

GAGUCCAUC

CAUCAGUC

CCAUCCAUC

AGUCAAAG

CCAUCAGUC

AAAGAAUG

AGAAUGGUU

CCAUCUGG

GAAUGGUUC

CAUCUGGA

GGUUCCAUC

UGGAGUCU

UCUGGAGUC

UTUAAUGUA

UGGAGUCUU

AAUGUAGA

GGAGUCUTUA

AUGUAGAA

CUUAAUGUA

GAAAGAAA

UGGAGACUU

GUAAUAAU

AGACUUGUA

AUAAUGAG

CtJUGUAAUA AUGAGCUA AGACUCCA CUGAUGA X GAA AUGGAACC UACAUUAA CUGAUGA X GAA ACUCCAGA UCUACAUU CUGAUGA X GAA AGACUCCA UUCUACAU CUGAUGA X GAA AAGACUCC UUUCUUUC CUGAUGA X GAA ACAUUAAG AUULAUUAC CUGAUGA X GAA AGUCUCCA CUCAUUAU CUGAUGA X GAA ACAAGUCU UAGCUCAU CUGAUGA X GAA AtJUACAAG 6623 UUUGUAAC CUGAUGA X GAA AGCUCAIU AUACAGUCA AAUGAGCUA GUUACAAA 6626 6627 6637 6640 6641 6644 6645 6650 6662 6674 6675 6682 6685 6687 6688 6693 6696 6697 6703 6704 6705 6719 6726 6743 6744 6747 6748 6749 6755 6756 6757 6764

CACUUTUGL

GCACUUTUC

UAAUGAAC

UUUUAAUC

AUUUUAAL

GCUAUUUU

UGCUALUU

UUCAGUGC

CAUGUUTUC

UAUCAGUU

UUIAUCAGU

UGGAAUAU

GALTUIGGAA

AUGAUTUGG

AAUGAUUG

UGGCAAAU

AAAUGGCA

UAAAUGGC

UUGUCAUA

UUUGUCAU

UUUUGUCA

UUAGUGCC

UUCUJEGU

CUGAAAGG

UCUGAAAG

AACUCUGA

AAACUCUG

GAAACUCU

AUCUCAGA

UAUCUCAG

UUJAUCUCA

ACGUACAU

ICUGAUGA

;CUGAUGA

"CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA I CUGAUGA CGAA ACUAGCUC GAA AACUAGCU GAA AGCACUUU GAA ACAAGCAC GAA AACAAGCA GAA AUGAACAA GAA AAUGAACA GAA AUUTUUAAU GAA AUUTUUCAG GAA AUUCAUGU GAA AAUTUCAUG GAA AUCAGUUA GAA AUUAUCAG GAA AUAUUAUC GAA AAUAUUAU GAA AUUGGAAU

GAA.AUGAUUGG

GAA AAUGAUUG GAA AUGGCAAA GAA AAUGGCAA GAA AAAUGGCA GAA ACCAUUUU GAA AGUGCCAA GAA AGUGCUCG GAA AAGUGCUC GAA AGGAAGUG GAA AAGGAAGU GAA AAAGGAAG GAA ACUCUGAA GAA AACUCUGA GAA AAACUCUG GAA AUCUCAGA

GAGCUAGUL

AGCUAGUUW

AAAGUGCUL

GUGCUUJGUL

UGCUUGUUC

UUGUUCAU

UGUUCALUA

AUUAAAAUA

CUGAAAAUU

ACAUGAAUU

CAUGAAUUA

UAACUGAUA

CUGAUAAUA

GAUAAUALU

AUAAUALUUC

ALUCCAAUC

CCAAUCALTJ

CAAUCAUUU

UUUGCCAUU

UUGCCAUUU

UGCCAUUUA

AAAAUGGUU

UUGGCACUA

CGAGCACU

GA GCACUUC CACUtJCCUU

ACUUCCULU

CU*UCCUUTJC

UTUCAGAGLU

UCAGAGUUUL

CAGAGUUTUC

UCUGAGAUA

J ACAAAGUG

CAAAGUGC

JGUTUCAUTUA

T CAUTUAAAA

AUUAAAAU

AAAAUAGc

AAAUAGCA

GCACUGAA

GAAACAUG

AACUGAUA

ACUGAUAA

AUAtJUCCA

UTUCCAAUC

CCAAUCAU

CAAUCAUU

AUUUG CCA

UGCCAUUUJ

GCCATJUUA

UAUGACAA

AUGACAAA

UGACAAA.

GGCACUAA

ACAAAGAA

CCUUYUCAG

CUUUCAGA

UCAGAGUU

CAGAGUUU

AGAGUUUC

UCUGAGAU

CUGAGAUA

UGAGAUAA

AUGUACGU

S

*5 S

S

S

6769 6781 6814 6820 6822 6825 6829 6851 6852 10 6855 6856 6857 6858 6872 6875 6876 6877 6880 6901 20 6910 6913 6917 6922 6925 6926 6927 6931 6935 6936 6951 6953 6954 6970

GUILJCCAC

UCCACCC

AAGACAC

ACLJGACAJ

GGACUGA(

CLUIGGACI

ACUUCUU(

CUAAAAL71

CCUAAAA.

GUCCCUAZ

GGUCCCU;

GGGUCCCL

CGGGUCCC

UAGGAAAC

GGCUAGGA

GGGCUAGG

LJGGGCUAG

LUGUGGGC

AUCUGUUU

CUAGCGAG

AGGCUAGC

AAUGAGGC

AUUUAAAU

UCAAUUUA

AUCAAULU

AAUCAAUJ

CULTUAAUC

ccUccUtUu uccUccTu

CGGCCAAA

GUCGGCCA

tGUCGGCC

CACACAGU

G CUGAUGA A CUGAUGA k. CUGAUGA k. CUGAUGA 2 CUGAUGA J CUGAUGA 3 CUGAUGA J CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

T CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA)

CUGAUGA

CUGAUGA)

CUGAUGA)

CUGAUGA Y CUGAUGA Y~ CUGAUGA Y CUGAUGA X X GAA ACAUtJAUC X GAA ACUGUIJCC K GAA ACUUGCAC K GAA ACACAGAC 'GAA AGACACAG 'GAA ACAAGACA GAA ACUGACAA C GAA ACAUCUCG rGAA

AACAUCUC

GAA AUUAACAU GAA AAtJUAACA GAA AAAUUAAC GAA AAAAUUAA GAA AGGCACGG GAA ACAAGGCA GAA AACAAGGC GAA AAACAAGG GAA AGGAAACA GAA AUGtJUUGC GAA AUCUGUUUL GAA AGUAUCUG GAA AGCGAGUA GAA AGGCUAGC GAA AUGAGGCU GAA AAUGAGGC GAA AAAUGAGG GAA AUtJUAAAU GAA AUCAAUUU GAA AAUCAAtJT GAA AUGCACUC GAA AGAUGCAC GAA AAGAUGCA GAA ACACCACU

GAUAAUGU

GGAACAGU

GUGCAAGU,

GUCUGUGUi CUGUGUCUIl

UGUCUUGU(

UTUGUCAGU(

CGAGAUGUT

GAGAUGU;

AUGUUAALR

UGUUAAUUI.

GUUAAUJEJI

UUAAUUTUUP

CCGUGCCUUL

UGCCUUGUU

GCCUUGUUU

CCUUGUJUUC

UGUUUCCUA

GCAAACAUC

AAACAGAUA

CAGAUACUC

UACUCGCUA

GCUAGCCUC

AGCCUCAUU

GCCUCAUUEJ

CCUCAUTUUA

AUUUAAAUU

AAAUUGAUU

AAUEJGAUUA

GAGUGCAUC

GUGCAUCUU

UGCAUCUUU

AGUGGUGUA

A CGUGGAAC C UGGGUGGA C UGUGUCTJI

UUGUCAGU

J GUCAGUCC 2AGUCCAAG 2CAAGAAGU J AAUUUUAG kALULTJUAGG J UUAGGGAC

JUAGGGACC

T AGGGACCC

GGGACCCG

GUUtJCCUA

UCCUAGCC

CCUAGCCC

CUAGCCCA

GCCCACAA

AAACAGAU

CUCGCUAG

GCUAGCCU

GCCUCAUU

AUUUAAAU

UAAAUUGA

AAAUUGAU

AAUUJGAUUJ

GAUTUAAAG

AAAGGAGG

AAGGAGGA

UUUGGCCG

UGGCCGAC

GGCCGACA

ACUGUGUG

7026 AACACACA CUGAUGA X GAA ACACCCAC GGGGUUUUUE GUGGGUGUA UGUGUGUU' 7034 7035 7036 7043 7047 7049 7050 7051 7065 7066 7067 7068 7073 7074 7077 7078 7079 7080 20 7082 7095 7097 7102 7108 7110 7124 7125 7129 7132 7134 7136 7137 7138

AUGCAMA

UAUGCAC)

LTUAUGCAC

UAAAUAG.

UCCIJUAAM

UUtccuu; GtUUUCCL

AGUUUCCL

AACUUTUA-Z

UAACUUTUA

GUAACUUUJ

AGUAACUU

AUAAAAGU

UAUAAAAG

UULGUAUAA

UUtJGUAUA

GUUTJGUAU

GGLTUUGUA

UIJGGUULUG

GUAGCAUA

CUGUAGCA

UAUAUCUG

CUGUCUtJA

GUCUGUCU

UAGGACCA

AUAGGACC

AAAUAUAG

UAGAAAUA

ACUAGAAA

UGACUAGA

AUGACUAG

CAUGACUA

k CUGAUGA k~ CUGAUGA

_CUGAUGA

J CUGAUGA

SCUGAUGA

CUGAUGA

JCUGAUGA

FCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA;

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA)

CGAA ACACACAU C GAA AACACACA IGAA AAACACAC [GAA AUJGCACAA 'GAA AGUUAUGC GAA AUAGUUAU GAA AAUAGUUA GAA AAAUAGUtJ GAA AUTUCCAGU GAA AAUTUCCAG GAA AAAUUCCA GAA AAAAUUCC GAA ACULTUAAA GAA AACUtJUAA GAA AGUAACUU GAA AAGUAACU GAA AAAGUAAC GAA AAAAGUAA GAA AUAAAAGU .GAA AUUCUUGG GAA AUAUUCUU GAA AGCAUAUA GAA AUCUGUAG GAA AUAUCUGU GAA ACCAUGUC GAA AACCAUGU GAA ACCAAACC GAA AGGACCAA GAA AUAGGACC GAA AUAUAGGA GAA AAUAUAGG GAA AAAUAUAG

AUGUGUGUL

UGUGUGUUL

GUGUGUJUCL

UTUGUGCAUP

GCAUAACUPA

AUAACUAUTU

UAACUAUUIJ

AACUAUUUA

ACUGGAAUU

CUGGAALUU

UGGAAUUUU

GGAAUUUUA

UUAAAGUU

UUAAAGUUA

AAGUUACLtJ

AGUUACULU

GUUACIUUU

UTUACUUUUA

ACUUUtJAUA

CCAAGAAUA

AAGAAUAUA

UAUAUGCUA

CUACAGAUA

ACAGAUAUA

GACAUGGUU

ACAUGGUUlJ GGtJUUGGUC

UUGGUCCUA

GGUCCUAUA

UCCUAUAUU

CCUAUAUUU

CUAUALTUUC

J UTUGUGCAU J UGUGCAUA

TGUGCAUAA

ACUAIJIJUA

UUUAAGGA

UAAGGAAA

AAGGAAAC

AGGAAACU

UUAAAGUU

UAAAGUTUA

AAAGUTUAC

AAGUUACU

ACUtJUUAU

CUUUUAUA

UUAUACAA

UAUACAAA

AUACAAAC

UACAAACC

CAAACCAA

UAUGCUAC

UGCUACAG

CAGAUAUA

UAAGACAG

AGACAGAC

UGGUCCUA

GGUCCUAU

CUAUAUUUJ

UAUUTUCUA

UtJUCUAGU

UCUAGUCA

CUAGUCAU

UAGUCAUG

7140 7143 7155 7157 7158 7159 7162 7164 7169 10 7171 7172 7175 7177 7180 7182 7185 7186 7192 7194 7195 7196 7198 7199 7202 7208 7209 7212 7215 7218 7225 7226 7229 7233

AUCAUGAC

UUCAUCATJ

AUACAAAA

GUAUACAA

GGUAUACA

UGGUAUAC

AGAUGGUA

GAAGAUGG

UAUAUGAA

ALTUAUAUG

UAUUAUAU

GUAUALTUA

AAGUAUAU

UUUAAGUA

UUUUUAAG

AUAUUUUU

AAUALUUJ

UUAAGAAA

AAUUAAGA

CAAUUAAG

CCAAEJUAA

UCCCAALU

AUCCCAAU.

CAAAUCCC

CGAUUACA

ACGAUTUAC

GGUACGAU

GUUGGUAC

UAAGUUGG

UAUCAAUtJ

UUAUCAAU

AGUULTUAUC

GCCAAGUU

CUGAUGA

CUGAUGA

*CUGAUGA

*CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

GAA AGAAAUAU rGAA ACUAGAAA GAA ACAUUCAU GAA AUACAUUC GAA AAUACAUU GAA AAAUACAU GAA ACAAAAUA GAA AUACAAAA GAA AUGGUAUA GAA AGAUGGUA GAA AAGAUGGU GAA AUGAAGAU GAA AUAUGAAG GAA AUUJAUAUG GAA AUAUUAUA GAA AGUAUAUU GAA AAGUAUAU GAA AULTLJUUAA GAA AUAUUUU GAA AAUAUUUU GAA AAAUAUUU GAA AGAAAUAU GAA AAGAAAUA GAA AUUAAGAA GAA AUCCCAAU GAA AAUCCCAA GAA ACAAAUCC GAA AUUACAAA GAA ACGAUUAC GAA AGUUGGUA GAA AAGUUGGU GAA AUTUAAGUU GAA AUCAAUUA 9

UUUCUAGUC

AUGAAUGUA

GAAUGUALU

AAUGUAUUU

AUGUAUUUUI

UAUUJUUGUA

UUTUUGUAUA

UAUACCAUC

UACCAUCUU

ACCAUCUUC

AUCUJUCAUA

CUUCAUAUA

CAUAUAAUA

UAUAAUAUA

AAUAUACUU

AUAUACUUA

UUAAAAAUA

AAAAAUAUU

AAAAUAUUU

AAAUAUUUC

AUAUUUCUU

UAUUUCUUA

tJUCUUAAUU

AUUGGGALU

UUGGGAJUU

GGAUTUUGUA

UUJUGUAAUC

GUAAUCGUA

UACCAACUU

ACC.AACUUA

AACUUAAUU

UAAUUGAUA

AUAUUUCUA GUCAUGAU

AUGAUGAA

UUUUTGUAtJ

UUGUAUAC

UGUAUACC

GUAUACCA

UACCAUCU

CCAUCUUJC

UUCAUAUA

CAUAUAAU

AUAUAAUA

UAAUAUAC

AUAUACU

UACUUAAA

CUUAAAAA

AAAAAUAU

AAAAUAUU

UUUCUUAA

UCUUAAUU

CUUAAUUG

UUAAUUGG

AAUUGGGA

AUUGGGAU

GGGAUUUG

UGUAAUCG

GUAAUCGU

AUCGUACC

GUACCAAC

CCAACUUJA

AAUTUGAUA

AUUGAUAA

GAUAAACU

AACUUGGC

se 7238 7249 7250 7251 7252 7256 7257 7261 7263 7266 7267 7271 7275 7276 7277 7278 7279 7285 7288 20 7291 7292 7308 7310 7311 7312 7313 7314 7315 7316 7317 7320 7325 7330

CAGTJGC

GAACAUA

AGAACAU

CAGAACAI

ACAGAACA

GGAGACA(

AGGAGAC2

UGGAAGGI

UAUGGAAC

AUtJUAUGC

AALUUAUC

GAAAAAU'L

UULTUGAA~z

AUUIJUGAP

UAUUUUG.A

GLJAUTUUG

AGUAUUUU

UGAAUUAG

UGUEJGAAU

CUUUGUUG

UCTJUUGLU

AAAAAAAA

GGAAAAAA

AGGAAAAA

UAGGAAAA

UUAGGAAA

UUAGGAA

UUUUAGGA

AtUUUUAGG

UATUUUUAG

GULUAUUU

UTJUGAGLU

C CUGAUGA A. CUGAUGA A. CUGAUGA i CUGAUGA k. CUGAUGA 3 CUGAUGA

CUGAUGA

k. CUGAUGA

CUGAUGA

CUGAUGA

CUJGAUGA

I CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA)

CUGAUGA

CUGAUGA

CUGAUGA Y~ CUGAUGA Y~ CUGAUGA Y X GAA AGUJUUAUC K GAA AGCAGUUG K GAA AAGCAGUU .K GAA AAAGCAGU GAA AAAAGCAG C GAA ACAUAAAA C GAA AACAUAAA [GAA ACAGAACA 'GAA AGACAGAA GAA AGGAGACA GAA AAGGAGAC GAA AUGGAAGG GAA AUUTUAUGG GAA AAUUUAUG GAA AAAUUUAU GAA AAAAUUUA GAA AAAAAULU GAA AUUUUGAA GAA AGUAUUUU GAA AUTUAGUAU GAA AAUTUAGUA GAA AGCUUULU GAA AGAGCUUU GAA AAGAGCUUT GAA AAAGAGCU GAA AAAAGAGC GAA AAAAAGAG GAA AAAAAAGA GAA AAAAAAAG GAA AAAAAAAA GAA AGGAAAAA GAA AUTUUAGG

GAUAAACU

CAACUGCUI

AACUGCLTUE

ACUGCUULTI

CUGCUTLUU.

tJUUUAUGULL

UUUAUGUUC

UGUtJCUGUC

UUCUGUCUC

UGUCUCCIJC

GUCUCCUUC

CCUUCCAUA

CCAUAAAUU

CAUAAAUUU

AUAAAUUU

UAAAUUUtU

AAAUUUUTUC

UJUCAAAAUA

AAAAUACUA

AUACUAAUU

UACUAAUUC

AAAAAGCUC

AAAGCUCUU

AAGCUCUUUJ

AGCUCUUtU

GCUCUUUUU

CUCLUUUTUU

UCTUUu.TU

CLUUUUUU

UUUUUUUUC

TJUUUUCCUA

CCUAAAAUA

J GGCAACUG J UUAUGUUC J UAUGUUCU J AUGUUCUG k. UGUUCUGU

JCUGUCUCC

UGUCUCCU

UCCUUCCA

CUUCCAUA

ICCAUAAAU

*CAUAAALU

AAULTUTJUC

*UUUCAAAA

UTUCAAAAU

UCAAAAUA

CAAAAUAC

AAAAUACU

CUAAUTUCA

AUUCAACA

CAACAAAG

AACAAAGA

UUUUuUUU

UUUTUUUCC

UUUUUCCU

UUUUCCUA

UUCCUAA

IJUCCUAAA

UCCUAAAA

CCUAAAAU

CUAAAAUA

AAAUAAAC

AACUCAAA

0 0*000* 0 00 00 0 AUAAAUUU CUGAUGA X GAA AGUUUAUU AAUAAACUC AAAUUUAU 7335 CAAGGAUA CUGAUGA X GAA AUUUGAGU 0 0000 4 66 64 0 0660 0 0 @000 0 600006 0 0 000600 .0 7336 7337 7339 7342 7345 7346 7347 7362 7363 7373 7374 7383 7385 7393 7397 7401 7403 74-04 20 7405 7406 7418 7424 7425 7428 7429 7430 7437 7440 7447 7448 7449 7450

ACAAGGAU

AACAAGGA

UAAACAAG

CUCUAAAC

CUGCUCUA

UCUGCUCU

CUCUGCUC

UUUUUCUU

GUUUTUUCU

CCAUUUCA

ACCAUUUC

UtUEJUUGA

AAUUUUUU

UAUUUAGC

AAAAUAUU

AUUGAAAA

CCAUTUGAA

UCCAUUTGA

UUCCAUEJG

UUIJCCAUtJ

CUAACAUU

GCUAAACU

AGCUAAAC

AUCAGCUA

AAUCAGCU

CAAUCAGC

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X GAA AAUUUGAG GAA AAAUUUGA GAA AUAAALUU GAA AGGAUAAA GAA ACAAGGAU GAA AACAAGGA GAA AAACAAGG GAA AULTJUUCU GAA AAUUUUUC GAA AGUUTUUUC GAA AAGUUUUU GAA ACCAUUJUC GAA AGACCAUU GAA AUUUUTUUG GAA AGCAAUUU GAA AULUJAGCA GAA AUAUUUAG GAA AAUAUUA GAA AAAUAUUU GAA AAAAUAUU GAA AGUULUUCC GAA ACAUUUAG GAA AACAUTUUA GAA ACUAACAU ACUCAAAUU

UAUCCTJUG

CUCAAAUUU

AUCCUUGU

UCAAAUUUA UCCUUtGtU AAAUUtJAUC CUUGUUUA UUtJAUCCUU GtJUUAGAG AUCCUUGUUI UAGAGCAG UCCUtJGUUU AGAGCAGA CCUUGUUUA GAG CAGAG AGAAAAAUU AAGAAAAA GAAAAAUUA AGAAAAAC GAAAAACUUT

UGAAAUGG

AA.AAACUU

GAAAUGGU

GAAAUGGUC

UCAAAAAA

AAUGGUCUC AAAAAAtU CAAAAAAUIJ GCUAAAUA AAAUUGCUA AAUAULUU UGCUAAAUA UUTUUCAAU CUAAAUAUU UUCAAUGG UAAAUAUUU

UCAAUGGA

AAAUAUUUU

CAAUGGAA

AAUAUUU-UC AAUGGAAA GGAAAACUA AAUGUUAG CUAAAUGUU AGULUAGC UAAAUGUUTA GUUUAGCU AUGUUAGUU

UAGCUGAU

UGUUAGUUU

AGCUGAUU

GUUTAGUUUA

GCUGAUUG

UAGCUGAUTU

GUAUGGGG

CUGAUtJGUA UGGGGUUUI UAUGGGGUU

UUCGAACC

AUGGGGUtJU

UCGAACCU

UGGGGUUUtJ CGAACCIU GGGGUUUUC GAACCUUU CUGAUGA X GAA AACUAACA -UGAUGA X GAA AAACUAAC CCCCAUAC CUGAUGA X GAA AUCAGCUA AAACCCCA CUGAUGA X GAA ACAAUCAG GGUUCGAA CUGAUGA X GAA ACCCCAUA AGGUUCGA CUGAUGA X GAA AACCCCAU AAGGUUCG CUGAUGA X G.AA AAACCCCA AAAGGUUC CUGAUGA X GAA AAAACCCC 7457 AAAAGUGA CUGAUGA X GAA AGGUUCGA 7456 7459 7463 7464 7465 7466 7469 7470 7473 7474 7475 -7476 7480 7482 7483 7484 7495 7499 7506 7509 7510 7515 7531 7532 7534 7541 7545 7547 7549 7550 7557

AAAAAGUG

CAAAAAGU

CAAACAAA

ACAAACAA

AACAAACA

AAACAAAC

GUAAAACA

GGUAAAAC

AUAGGUAA

AAUAGGUA

AAAUAGGU

GAAAUAGG

LUGUGAAA

AGUUGUGA

CAGUUGUG

ACAGUUGU

UGGCAALU

UUAUUGGC

ACAGGAAU

UGGACAGG

AUGGACAG

UEJUUCAUG(

CACUGGAUC

ACACUGGAC

CUACACtIGC AAUAUAUC

C

GUCAAAtJA C UGGUCAAA c GAUGGUCA

C

UGAUGGUC C CAUAGGGU C CUGAUGA X GAA AAGGUUCG CUGAUGA X GAA AAAGGUUC CUGAUGA X GAA AGUGAAAG CUGAUGA X GAA AAGUGAAA CUGAUGA X GAA AAAGUGAA CUGAUGA X GAA AAAAGUGA CUGAUGA X GAA ACAAAAAG CUGAUGA X GAA AACAAAA'A CUGAUGA X GAA ACAAACAA CUGAUGA X GAA AACAAACA CUGAUGA X GAA AAACAAAC CUGAUGA X GAA AAAACAAA CUGAUGA X GAA AGGUAAAA CUGAUGA X GAA AUAGGUAA CUGAUGA X GAA AAUAGGUA CUGAUGA X GAA AAAUAGGU CUGAUGA X GAA ACACAGUUI CUGAUGA X GAA AUUTUACAC CUGAUGA X GAA AUIJGGCAA CUGAUGA X GAA AUUAUUGG :UGAUGA X GAA AAUJIAUUG :UGAUGA X GAA ACAGGAAU UGAUGA X GAA AUUUGCAU UTGAUGA X GAA AAUUUGCA UTGAUGA X GAA AUAAUUEJG UGAUGA X GAA ACACUGGA UGAUGA X GAA AUCUACAC UGAUGA X GAA AUAUCUAC UGAUGA X GAA AUAUAUCU 'UGAUGA X GAA AAUAUAUC UGAUGA X GAA AUGGUCAA UCGAACCUU UCACtUUUJ CGAACCUU

CACUULUU

GAACCUUUC

ACUUUUUG

CUUUCACUU

UUUGUUUG

UUUCACUUU UtJGUUJUGU tJUCACUUUU UGtUtUGUU UCACUUUUU GUUUGtUU CULUUUJGUU UGtJUUUAC UUUUUGUUtJ

GUUUUACC

UUGUUIJGUU

UUACCUAU

UGUUUGUUU

UACCUAUU

GUUUGULTUU

ACCUAUUU

UUUGUUUETJA

CCUAUUEJC

UUJUUACCUA tUtJCACAA UUACCUAUU

UCACAACU

UACCUAUUtJ

CACAACUG

ACCUAUIJUC

ACAACUGU

AACUGUGUA

AAUUGCCA

GUGUAAAUU

GCCAAUAA

UUGCCAAUA

AUUCCUGU

CCAAUAAUU

CCUGUCCA

CAAUAAUUC

CUGUCCAU

AIJUCCUGUC

CAUGAAAA

AUG CAAAUU AUCCAGUG UGCAAAULJA

UCCAGUGU

CAAAUTJAUC

CAGUGUAG

UCCAGUGUA

GAUAUAUU

GUGUAGAUA

UAUEJUGAC

GUAGAUAUA UtIUGACCA AGAUAUAUU

UGACCAUC

GAUAUAUTUU

GACCAUCA

UUGACCAUC

ACCCUAUG

AUCACCCUA UGGAUAUTJ 7563 AAUAUCCA CUGAUGA X GAA AGGGUGAU 7569 CUAGCCAA CUGAUGA X GAA AUCCAUAG CAGAAUGCA CUAUGGAUA UUGGCUAG 0 0:0.

10 7 7 7 7 7 7 7 7 7 7' 7 74 7' 74 7571 AACUAGCC 7576 GGCAAAAC 7579 AAAGGCAA 7580 UAAAGGCA 7581 AUAAAGGC 7586 GCUUAAUA 7587 UGCIJUAAU 7588 UUGCUUAA 7590 AUUtJGCUU 7591 AAUUIJGCU 7599 CUGAAAUG 7600 GCUGAAAU 7603 CAGGCUGA 1604 UCAGGCUG 1605 TUCAGGCU p617 UAUAGGCA p623 AGAAUAUA '625 AGA.GAAUA '627 GCAGAGAA 629 GAGCAGAG 630 AGAGCAGA 632 AAAGAGCA 637 AAUACAAA( 639 AGAAUACAC 640 GAGAAUAC C 643 AAGGAGAA C 645 CAAAGGAG

C

646 UCAAAGGA C 648 GUUCAAAG C 651 CGGGUUCA C 652 ACGGGUtCC 661 GAUGUUUU C

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA

CUGAUGA

7UGAUGA

:UGAUGA

7UGAUGA I 7UGAUGA2

UGAUGA

UGAUGA

UGAUGA

:UGAUGA

:UGAUGA Y~ UGAUGA Y UGAUGA X UGAUGA X X GAA AUAUCCAU K GAA AGCCAAUA K GAA ACUAGCCA GAA AACUAGCC GAA AAACUAGC GAA AGGCAAAA C GAA AAGGCAAA [GAA AAAGGCAA 'GAA AUAAAGGC GAA AAUAAAGG GAA AUULUGCU GAA AAUUUGCU GAA AUGAAULU GAA AAUGAALU GAA AAAUGAAU GAA ACAUUCAG GAA AGGCAGAC GAA AUAGGCAG GAA AUAUAGGC GAA AUAUAUAG GAA AATJAUAUA GAA AGAAUAUA GAA AGCAGAGA GAA AGAGCAGA GAA AAGAGCAG GAA ACAAAGAG GAA AUACAAAG GAA AAUACAAA GAA AGAAUACA GAA AGGAGAAU GAA AAGGAGAA GAA ACGGGUUC

AUGGAUAU

UAUUGGCUJ

UGGCUAGU1I

GGCUAGUUL

GCUAGUUtn

UUUUGCCT.

UUUGCCUUL

UTUGCCUUTA

GCCUJTJAUU

CCUUUAUUA

AAGCAAAU)

AGCAAAUUC

AAAUUCAUU

AAUUCAtJTJU

AUJUCAUUTUC

CUGAAUGUC

GUCUGCCUA

CUGCCUAUA

GCCUAUAUA

CUAUAUAUU

UAUAUAUUC

UAUAUtJCUC

UCUCUGCUC

UCUGCUCUU

CUGCUCUUU

CUCUUTUGUA

CUTUUGUAUU

UTUUGUAUUC

UGUAUUCUC

AL7UCUCCUU

UUCUCCUUU

GAACCCGUU

J GGCUAGUU GUUtJUGCC J UUGCCUU

JUGCCUUUA

J GCCUUUAU

JUAUUAAGC

T AUUAAGCA

LUUAAGCAA

IAAGCAAAU

*AGCAAALU

*CAUTUUCAG

AUTUUCAGC

UCAGCCUG

CAGCCUGA

AGCCUGAA

UGCCUAUA

UAUAUUCU

UAUUCUCU

UUCUCUGC

CUCUGCUC

UCUGCUCU

UGCUCTJ

LUUGUAUU

UGUAUTUCU

GUAUUCUC

UUcUcuu

CUCCIUUG

UCCUUUGA

CtJUUGAAC

UGAACCCG

GAACCCGU

AAAACAUC

7662 GGAUGUUU CUGAUGA X GAA AACGGGUU AACCCGUTUA AAACAUCC 7669 UGCCACAG CUGAUGA X GAA AUGTJUUUA UAAAACAUC CUGtJGGCA Where "IX" represents stem II region of a HH ribozyme (Hertel et al., 1992 Nucleic Acids Res. 20 3252). The length of stem II may be 2 base-pairs.

0 1 0 a a a. a a a a a. a a. a. *a a aa a a a a a a a a. a a *aa 0 TEable III: Human fltl VEGF Receptor-Hairpin Ribozvme and Substrate Sequ1ence nt.

Position 16 39 180 190 278 290 295 298 302 420 486 C 537 565 721 C 786 C HP Ribozyme Sequence Substrate CGGGGAGG AGAA GAGAGG

CCGCUCCG

CCGCCAGA

AACGACCC

GCGCGCAC

GACAGCUG

AGCAGAC

3AGAAGCA

:UGUGAGA

:AUUUAUG

:UUCCACA

JUUGCUUG

~UAUU UGC GUAA C CC GULUUC C

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCCGCC

GUCCUC

GCCAGA

GGACCC

GCGCGC

GAGCAG

GCUGAG

GACAGC

C CUUC C

GAUUUA

GUGUUC

GUAGAA

GGGAAU

GGGAUC

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUTUGUGGUACAILrJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA

ACCAGAGAAACACA.CGUUGUGUGUACAUUACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJIJCUGUACAUUACCUGGUA

ACCAGAGAXA.CACACGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGILrJGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

CCUCUCG

GGCGGCG

GAGGACG

UCUGGCG

GGGUCCU

GCGCGCU

CUGCUCA

CUCAGCU

GCUGUCU

GGAAGCA

UAAAUCU

GAACACA

IJUCUACA

AUUCCCU

CCU

GCU

CAC

GCC

GCU

GCU

GCU

GUC

GCU

GCC

GCC

CCU

CC

CCUCCCCC

CGGAGCGG

UCUGCCGG

GGGUCGUU

GUGCGCGC

CAGCUCUC

GUCUGCUU

UGCUUCUC

UCUCACAG

CAUAAAUG

UCUGGAAG

CAAGCAAA

GCAAAUAU

GGULJACG

863 83 CUUCACAG AGAA GAAGCC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GCCUUCU CAC CUGUGAAG

S

S

S S S S 55 5 5 S* S5 S* S S S S S 5*S 55 55 S S S. 55 55 5 55 S S S S S S S S S S S S S S S. 5 5 555 5 0 1056 UttUUUC AGAA GGGUAA ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA 1301 1310 1389 1535 1566 1572 1604 1824 1908 1949 1973 2275 2321 2396 2490 2525 2625 2652

GCCGGUAA

UCAUAGAG

AAAUAGCG

UUUCGUAA

AGAGCCGG

GGGUAGAG

CGGUACAA

AUUCUAGA

UUUGGCAC

cUccuucc

CUGUGCAA

AGUGGUGG

ACCAAGUG

UUUCAAUA

GUUCCUUG

UUAGAGUG

.GAUAGGUA

GGAACUUC

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCUUGC

GGUAAG

GAUUUC

GGGGUU

GGAAAC

GGGUCU

GGAUUU

GCCACA

GUGAUA

GCAUUU

GUU-UCA

GCUGAU

GAGGCU

GCGUGC

GUGAGG

GCUCCA

GUCULU

GGGUCC

ACCAGAGAAACACACGJTGUGGUACAUrJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUUTACCUGGUA

ACCAGAGAAA~CACACGUUIGUGGUACAUUJACCUGGUA

ACCAGAGAIAACACACGIUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUU1ACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUGUGGUACAUJTACCUGGUA

ACCAGAGAXAACACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAACACACGUUGJUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

UUACCCU GAU GAAAAAAA GCAAGCG GUC UUACCGGC CUUACCG GCU CUCUAUGA GAAAUCU GCU CGCUAUUU AACCCCA GAU UUACGAAA GUUUCCA CAC CCGGCUCU AGACCCG GCU CUCUACCC AAAUCCU GAC UUGUACCG UGUGGCU GAC UCUAGAAU UAUCACA GAU GUCCCAAA AAAUGCC GAC GGAAGGAG UGAAACU GUC UUGCACAG AUCAGCA GUl CCACCACU AGCCUCA GAU CACUUGGU GCACGCU GUU UAUUGAAA CCUCACU GUl CAAGGAAC UGGAGCU GAU CACUCUAA AAAGACU GAC UACCUAUC GGACCCA GAU GAAGTJUCC S. S S S* S S S S S. S S *SS

S

2684 2816 2873 2930 2963 3157 3207 3211 3245 3256 3287 3402 3580 3641 3655 3810 3846 3873 3995 CAUAAGGG AGAA GCUCAC ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA GUGAGCG GCU CCCUUAUG

CAGCCACA

GCUCAGUC

AGGCUCCC

CAAUCACC

UUCCUGAA

UAGAAAC C

CUUGUAGA

UGUAAGAA

CACUUGAA

UUCUGGAA

CUCACAUA

CCUCAGGC

CCAGCAUG

UCUGUGCC

UCAGAGAA

AACUUCGG

CUGACAUC

GAGAGGCC

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

A~GAA

AGAA

GGCACG

GAGCUU

GGUUAA

GAGGCC

GGAGCU

GAAUCC

GUCAGA

GAUCUU

GUAAGA

GGAACU

GGGUUJC

GCAAAA

GAUAGA

GUCCAG

GGAGUU

GAAAUA

GAGCUU

GAGUGC

ACCAGAGAAACACACGUUGUGGUACAIJUACCUGGUA

ACCAGAGAAACACACCUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUYJACCUGGUA

ACCAGAGAAACACACGUJYGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUrACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJIGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACATTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACALPJACCUGGUA

ACCAGAGAAACACAGUJGUGGUACAUUACCUGGUA

CGUGCCG

AAGCUCU

UUAACCU

GGCCUCU

AGCUCCG

GGAUUCU

UCUGACG

AAGAUCU

UCUUACA

AGUC C U

GAACCCC

UUUUTGCA

UCUAUCA

CUGGACU

AACUCCU

UAUUUCA

AAGCUCU

GCACUCU

GAC

GAU

GCU

GAU

GCU

GAC

GIU

GAU

GUU

GUC

GAU

GUC

CAU

GCU

GCC

GCU

GAU

GUU

UGUGGCUG

GACUGAGC

GGGAGCCU

GGUGAUUG

IJUCAGGAA

GGUUUCUA

UCUACAAG

UUCUUACA

IJUCAAGUG

UUCCAGAA

UAUGUGAG

GCCUGAGG

CAUGCUGG

GGCACAGA

UUCUCUGA

CCGAAGUU

GAUGUCAG

GGCCUCUC

a a a 4100 4104 4120 4135 4210 4217 4224 4382 4385 4537 4573 4594 4628 4636 4866 4871 4905 5233 5281 UGACAUCA AGAA GCCCCG ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA CGGGGCU GUC UGAUGUCA

CUGCUGAC

AUGGCAGA

GUGCCCAC

GGGCGGG

ACUCUGGG

GAGUUGUA

CAAAAAGC

UCACAAAA

GGGGUUGG

CUCAAUCA

AUUGGGUG

GGCUGCAG

GGGUUUUG.

AGGGUCAG

GUAGAAGG

CGCUGUCC

CUGUGCAA

CUCCUCAG

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GACAGC

GGGCCU

GGAAUG

C CA CC

GGGAGC

GCGGGC

GCCUCC

GCUGCC

GGGAAG

GGUCCU

CUGCAG

GGCCCA

GCAGGG

CGGAAG

CAGCUC

GCUCCU

GAAUAA

GCAUUJ

ACCAGAGAAAcACACGUUTGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGUACAUUTACCUGCUA

ACCAGAGAAACACACGUUGUCGUACAUUIACCUGGUA

ACCAGACAAACACACGUUCUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGU1JGUGGUACAUUACCUGGUA

ACCAGACAAACACACGUTJGUGCUACAUUACCUGCUA

ACCAGAGAAACACACGUUGUCGUACAUUACCUGCUA

ACCAGAGAAACACACCUUGUGGUACAUUACCUCGUA

ACCACAGAAACACACGUyJGUGGUACAUUACCUGGUA

ACCACACAAACACACGUIJCUGCUACAUUACCUGGUA

ACCAGACAAACACACGUrJGUGGUACAUUTACcCGUA

ACCACAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCACAGAAACACACCUUGUGGUACAUJACCUCCUA

ACCAGAGAAACACACGUUGJUGGUACAUUACCUGCUA

ACCACAGAAACACACGUUTGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

GCUCUCU

AGGCCCA

CAUUCCA

GCGUGCU

GCUCCCC

G CCC CCA

GGAGCCA

CCCAGCU

C UUC CCU

AGGACCA

CUGCACU

UGGGCCA

CCCUGCA

CUUCCCA

CAGCUCU

AGGAGCA

UUAUUCU

AAAUGCA

GAU

C-UU

CCU

CCU

GCC

GAC

CCU

GCU

GCU

C-UU

CAU

GCC

CC

CCU

GAC

CAU

C-U

GUC

GUCACCAG

UCUGCCAU

CUGGGCAC

CCCCGCCC

CCCAGACU

UACAACUC

GCUUUUUG

UUUUGUGA

CCAACCCC

UGAUUGAG

CACCCAAU

CUGCACC

CAAAACCC

CUGACCCU

CCU-UCUAC

GGACAGCG

UTUGCACAG

CUGAGGAG

0*O* 6*

I

I. I I I I I I I I I 5319 5358 5392 5563 5622 5738 5838 5933 6022 6120 6163 6270 6412 6511 6778 6826 7245 7258 7433 uUUcCUCc

GGUAUAGA

UGGGUCCC

UGAGUCCC

AGUUUCAA

UAGCAUCA

UAGCAUCA

CCCCAAGA

CACAUAAG

UCCACAAA

GUGGAGAG

AAAUUGCC

AAGACAUG

UUUGAAGG

UC CA C CCA ACtJUCUUG

AACAUAAA

UGGAAGGA

CCCAUACA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

PiGAA

AGAA

GCCCUC

GGGUCU

GUGIJUG

GGAGAA

GUUGAA

GAGCCA

GAGCCA

GCAAUC

GAGGCA

GCUGCC

GUCCCA

GUCACA

GCUAAG

GAGUAA

GUUCCA

GACAAG

GUUGCC

GAACAU

GCUAAA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGCUA

ACCAGAGAAACACACGUJIGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGILrJGUGGUACAUUACCUGGUA

ACCAGAGAAA.CACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAAA~CACACGUIJGUGGUACAUUrACCUGGUA ACCAGAGAAACACACGU1JGUGGUACAUUIACCUGGUA

ACCAGAGAACACACGUUIGUGGUACAUUTACCUGGUA

AC CAGAGAAA CA CA CGUJGUGG UACAU!UA CCUGG UA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUrJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAACACACGUUrGUGGUACAUJACCUGGUA

GAGGGCU

AGACCCC

CAACACA

UUCUCCA

UUCAACU

UGGCUCU

UGGCUCU

GAUTUGCU

UGCCUCU

GGCAGCG

UGGGACA

UGUGACA

CUUAGCU

UlJACUCA

UGGAACA

CUUGUCA

GGCAACU

AUGUUCU

UIJUAGCU

GAU

GUC

GUU

c-UU

GCU

GUU

GUt)

GCU

GUt)

GCU

GUC

GCU

GUU

GCU

GUC

GUC

GCU

GUC

GAU

GGAGGAAA

*UCUAUACC

*GGGACCCA

GGGACUCA

UUGAAACU

UGAUGCUA

UGAUGCUA

UCUTUGGGG

CUUAUGUG

tJUUGUGGA

CUCUCCAC

GGCAAUUU

CAUGUCUU

CCUUCAAA

UGGGUGGA

CAAGAAGU

UUUAUGU

UCCUUCCA

UGUAUGGG

*0 *0 .II :0 0 7512 7606 7618 7633 IJUUUCAUG AGAA GGAAUU ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA GACAUUCA AGAA GAAAUG ACCAGAGAAACACACGUJGUGGUACAJTUACCUGGUA AAUAUAUA AGAA GACAUU ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA AUACAAAC AGAA GAGAAU ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA AAUUCCU GUC CAUGAAAA CAIJUUCA CCC UGAAUGUC AAUGUCU GCC UAUAUAUU ATJUCUCU GCU C12JTUGUAU Table IV: Human KDR VEGF Receptor-Hammerhead Ribozyme and Substrate Seauence nt Position HH R'ibozyme Sequence Substrate 10 15 20 1 21 CACAGGGC 33 UCCACGCA 56 AACCCACA 64 ACUAGGCA 65 CACUAGGC

AGAAACAC

75 UCAAGAGA 76 AUCAAGAG 77 GAUCAAGA 79 CAGAUCAA 81 GGCAGAUC 35 CCUGGGCA 96 UGUAUGCU 102 UCUUULTJG Li14 AUUGUAAG Li7 UUAAUUGU .18 CUtJAAUUG .23 UTJAGCCUU .24 AUUAGCCU .30 AGtJUGUAU .33 AAGAGUUG 39 AAUU-UGAA 41 GUAAUUUtG 42 AGUAAUUUC 47 CUGCAAGUC 48 CCUGCAAGC

CUGATJGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

:UGAUGA:

7UGAUGA 7UGAUGA 7UGAUGA

~UGAUGA

.UGAUGA

C GAA ACGGCCAG I GAA AGCCACAG GAA AGGCGGCC GAA ACCCACAG GAA AACCCACA GAA AGGCAAAC GAA ACACUAGG GAA AACACUAG GAA AAACACUA GAA AGAAACAC GAA AGAGAAAC GAA AUCAAGAG GAA AGCCUGGG GAA AUGCUGAG GAA AUGUCUUUJ GAA AGUAUGUC GAA AAGUAUGU GAA AUUGUAAG GAA AAUUGUAA GAA AGCCUUAA GAA AUUAGCCU GAA AGUUGUAU GAA AGAGUUGU GAA AAGAGUUG GAA AUTUUGAAG GAA AAUUUGAA

CUGGCCGU(

CUGUGGCUC

GGCCGCCUC

CUGUGGGUI

UGUGGGUUL

GUUUGCCUP

CCUAGUGUL

CUAGUGUUU

UAGUGUUUC

GUGUUUCUC

GULTUCUCUU

CUCUUGAUC

CCCAGGCUC

CUCAGCAUA

AAAGACAUA

GACAUACUU

ACAUACUUA

CUUACAAUU

UUACAAUUA

UUAAGGCUA

AGGCUAAUA

AUACAACUC

ACAACUCIU

CAACUCUUC

CUtJCAAAUU

LTUCAAALUUA

GCCCUGJG

UGCGUGGA

UGUGGGUU

J UGCCUAGU

JGCCUAGUG

GUGUUTUCU

UCUCtIUGA

CUCUUGAU

UCUUGAUC

LUJGAUCUG

GAUCUGCC

UGCCCAGG

AGCAUACA

CAAAAAGA

CUUACAAU

ACAAUTUAA

CAAUUAAG

AAGGCUAA

AGGCUAAU

AUACAACU

CAACUCtU

UUCAAALU

CAAAUUAC

AAAUUACU

ACUTUGCAG

CUUGCAGG

151 UCCCCUGC CUGAUGA X GAA AGUAAUUU AAAUUACUU GCAGGGGA 170 GCCAGUCC CUGAUGA X GAJ o

S

S

*5*S

S

S

S

S

@55.5.

180 181 190 193 243 245 246 250 10 258 264 265 276 296 15 305 306 308 323 329 20 333 336 337 338 342 344 348 349 355 356 362 364 368 369 UUGGGCC2

AUUGGGC(

ACtJCUGAT

GCCACUCI

UUACAGAI

UCUUACAC

GUCUUAC;

GAGUGUCL

GGAAUUGL

ACULUGG

CACULUJUG

UCATUUCC

AGCACLTLJG

CCCGGUAG

UCCCGGUA

UUCCCGG

CCGAGGCC

AAAUGACC

ACAUAAAU

UAGACAUA

AUAGACAU

CAUAGACA

UGAACAUA

CUUGAACA

UAAUCUUG

GUAAUCUU

AGAUCUGU

GAGAUCUG

UAAAUGGA

AAUAAAUG

AAGCAAUA

GAAGCAAU

~CUGAUGA

CUGAUGA

J CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

FCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CIJGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2 CUGAUGA2

CUGAUGA

C GA) C GAI I GI)

GAI

GA)

GA)

GAJ

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

~AGUCCCUC

SAGCCAGUC

\AAGCCAGU

SAUUGGGCC

AUTUAUUGG

SAGGCCAUC

AGAGGCCA

AAGAGGCC

ACAGAAGA

AGUGUCUU

AUtJGUGAG

AAUUGUGA

AUCACtTUU

AGGCUCCA

AGCACUUG

AAGCACUU

AGAAGCAC

AGUCAGUtJ

AGGCCAAG

ACCGAGGC

AUGACCGA

AAUGACCG

AAAUGACC

ACAUAAAU

AGACAUA\

ACAUAGAC

AACAUAGA

AUCUUGAA

AAUCUUGA

AUCUGUAA

AGAUCUGU

AUGGAGAU

AAUGGAGA

GAGGGACUT

GACUGGCUT

ACUGGCIJ!Jt

GGCCCAAUI

CCAAUAAUC

GAUGGCCUC

UGGCCUCLTL

GGCCUCUUC

UCUUCUGUA

AAGACACUC

CUCACAAUU

UCACAAUTUC

AAAGUGAUC

UGGAGCCUA

CAAGUGCUU

AAGUGCUUC

GUGCUTJCUA

AACUGACUTJ

CUJUGGCCUC

GCCUCGGUC

UCGGUCAUTJ

CGGUCAUUU

GGUCAIJUUA

AUTUUAUGUC

UTUAUGUCUA

GUCUAUGUU

UCUAUGUTUC

UUCAAGAUU

UCAAGAIJUA

tJUACAGAUC

ACAGAUCUC

AUCUCCAtU UCUCCAUUtJ J GGACUGGC J UGGCCCAA J GGCCcAAU

SAUCAGAGU

AGAGUGGC

UUCUGUAA

CUGUAAGA

UGUAAGAC

AGACACUC

ACAAUUCC

CCAAAAGU

CAAAAGUG

GGAAAUGA

CAAGUGCU

CUACCGGG

UACCGGGA

CCGGGAAA

GGCCUCGG

GGUCAUUU

AUUTUAUGU

UAUGUCUA

AUGUCUAU

UGUCUAUG

UAUGUUCA

UGUTUCAAG

CAAGAUTUA

AAGAUEJAC

ACAGAUCU

CAGAUCUC

UCCALTUUA

CAUUFJAUU

UAUTUGCUU

AUUTGCLTUC

.9 9 6 9~*9*9

S

9.

9 9 0* 86 9 9999 9 .9 9 6

J..

370 372 376 377 381.

382 399 404 408 10 409 438 439 445 447 452 456 457 458 463 20 465 473 477 478 488 503 504 507 508 517 525 526 527 548 AGAAGCAj

ACAGAAG(

ACUAACAC

CACUAACZ

UGGUCACt UtJGGUCAC

AUGUACAC

CAGUAAUC

UUCUCAGL

GUUCUCAG-

AGACAUGG

GAGACAUG

GGACCCGA

AUGGACCC

UUGAAAUG

AGALUUJGA

GAGALUJUG

UGAGALUU

CACGUUGA

GACACGUUJ

CACAAAGU

CUUGCACA

UCIJUGCAC

UtJUCUGGG

CAGGAACA

UCAGGAAC

CCAUCAGG

ACCAUCAG

AAUUCUGU

UCCCAGGA

GUCCCAGG

UGUCCCAG

GAAUAGUA

k. CUGAUGA

:CUGAUGA

3CUGAUGA k. CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

FCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA2

CUGAUGA

CUGAUGA?

CUGAUGA

CUGAUGA 2 CUGAUGA Y~ CUGAUGA Y CUGAUGA Y K GAA AAAUGGAG K GAA AUAAAUGG K GAA AGCAAUAA K GAA AAGCAAUA C GAA ACAGAAGC C GAA AACAGAAG C GAA ACUCCAUG CGAA ACACGACU GAA AUGUACAC GAA AAUGUACA GAA AUCACCAC GAA AAUCACCA GAA ACAUGGAA GAA AGACAUGG GAA ACCCGAGA GAA AUGGACCC GAA AAUGGACC GAA AAAUGGAC GAA AUUUGAAA GAA AGAUtJEGA GAA ACACGtJUG GAA AGUGACAC GAA AAGUGACA GAA AUCUUGCA GAA AUCUCUUU GAA AAUCUCUU GAA ACAAAUCU GAA AACAAAUC GAA ACCAUCAG GAA AUTUCUGLTU GAA AAUUCUGU GAA AAAUUCUG GAA AGCCCUUC

CUCCAUMU

CCAUUUAUI

UUAUUGCUI

UAUUGCUU(

GCUUCUGIUt

CUUCUGTUU;

CAUGGAGUC

AGUCGUGUP

GUGUACAUL

UGUACAUUA

GUGGUGAUU

UGGUGALTUC

UUCCAUGUC

CCAUGUCUC

UCUCGGGUC

GGGUCCAUU

GGUCCAUJU

GUCCAUUUC

ULTUCAAAUC

UCAAAUCUC

CAACGUGUC

GUGUCACUrJ

UGUCACLUU

UGCAAGAUA

AAAGAGAUTJ

AAGAGAtUUU

AGAUIJUGUUT

GAUTUUGUTUC

CUGAUGGUA

AACAGAAUU

ACAGAAUUU

CAGAAUUTUC

GAAGGGCUU

UUGCTJUCU

J GCUUCUGU J CUGUUAGU

-UGUUAGUG

J AGUGACCA

GUGACCAA

GUGUACAU

LCAUtJACUG

IACUGAGAA

CUGAGAAC

CCAUGUCU

CAUGUCUC

UCGGGUCC

GGGUCCAU

CALTULJCAA

UCAAAUCU

CAAAUCUC

AAAUCUCA

UCAACGUG

AACGUGUC

ACUUUGUG

UGUGCAAG

GUGCAAGA

CCCAGAAA

UGUtJCCUG

GLTUCCUGA

CCUGAUGG

CUGAUGGU

ACAGAAUU

UCCUGGGA

CCUGGGAC

CUGGGACA

UACUAUUC

99t*b* 9

S

'9.59.

9 100

C

549 550 553 555 556 563 570 575 588 590 591 606 607 619 620 626 628 630 631 20 635 639 642 645 648 651 656 658 663 664 665 675 676

GGAAUAGU

GGGAAUAG

GCUGGGAA

UAGCUGGG

GUAGCUGG

UGAUCAUG

GCAUAGCU

UGCCAGCA

UCACAGAA

CUCACAG

GCUUCACA

UCAUCAUU

UUCAUCAU

AGACUGGU

UAGACUGG

ACAUAAUA

GUACAUAA

AUGUACAU

UAUGUACA

CAACUAUG

ACGACAAC

ACAACGAC

CCUACAAC

UACCCUAC

CUAUACCC

AAAUCCUA

AUAAAUCC

ACAUCAUA

CACAUCAU

CCACAUCA

GGACUCAG

CGGACUCA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CtJGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAA AAGCCCJU GAA AAAGCCCU GAA AGUAAAGC GAA AUAGUAAA GAA AAUAGUAA GAA AGCUGGGA GAA AUCAUGUA GAA ACCUGAUC GAA ACCAUGCC GAA AGACCAUG GAA AAGACCAU GAA AUUUtJUGC GAA AAUUUUEJG GAA ACUUUCAU GAA AACUUUCA GAA ACUGGUAA GAA AGACUGGU GAA AUAGACUG GAA AAUAGACU GAA ACAUAAUA GAA AUGUACAU GAA ACUAUGUA GAA ACAACUAU GAA ACGACAAC GAA ACAACGAC GAA ACCCUACA GAA AUACCCUA- GAA AUCCUAUA GAA AAUCCUAU GAA AAAUCCUA GAA ACCACAUC GAA AACCACAU

AAGGGCUUL

AGGGCUUUW

GCLTUUACUP

LUUACUAUL

UUACUAUJC

UCCCAGCUA

UACAUGAUC

GAUCAGCUA

GGCAUGGUC

CAUGGUCUU

AUGGUCUUC

GCAAAAAUU

CAAAAAUUA

AUGAAAGUU

UGAAAGUUA

UTUACCAGUC

ACCAGUCUA

CAGUCUAUU

AGUCUAUUA

UAUUAUGUA

AUGUACAUA

UACAUAGUU

AUAGUUGUC

GUTUGUCGUU

GUCGLUGUA

UGUAGGGUA

UAGGGUAUA

UAUAGGAUU

AUAGGAUUEJ

UAGGAUUUA

GAUGUGGUU

AUGUGGUUJC

J ACUATJUCC

LCUAUUTCCC

LUUCCCAGC

fCCCAGCUA

CCAGCUAC

CAUGAUCA

AGCUAUGC

UGCUGGCA

LTUCUGUGA

CUGUGAAG

UGUGAAGC

AAUGAUGA

AUGAUGAA

ACCAGUCU

CCAGUCUA

UAUUtAUGU

UUAUGUAC

AUGUACAU

UGUACAUA

CAUAGUTUG

GUUGUCGU

GUCGUUGU

GUUGUAGG

GUAGGGUA

GGGUAUAG

UAGGALUU

GGAUUUIAU

UAUGAUGU

AUGAUGUG

UGAUGUGG

CUGAGUCC

UGAGUCCG

0 682 AUGAGACG CUGAUGA X GAA ACUCAGAA UUCUGAGUC CGUCUCAU 686 ULJCCAUGA CUGAUGA X GAA ACGGACUC GGCGCUAGA GAGUCCGUC UCAUGGAA .0 0 0 00 0 :0 688 696 702 704 708 720 723 725 726 730 733 750 762 767 768 779 784 785 20 787 788 796 802 810 813 825 836 857 858 859 860 869

AAUUCCAUJ

GAUAGUC

CCAACAGA

CUCCAACA

uuuuCcC

UUUAAGAC

CAAUTUUAA

UACAAUUU

GUACAALU

UGCUGUAC

UCLTUGCtJG

CCCACAUU

UUJGAAGUC

CCCAGUUG

UCCCAGUU

AAGAAGGG

CL71JCGAAG

GCUUCGAA

AUGCUUCG

GAUGCUUC

CUUAUGCU

AAGLTUUCU

CGGUUUAC

UCUCGGU

UGGGUUUU

CACUCCCA

UGCUCAAA

GUGCUCAA

GGUGCUCA

AGGUGCUC

CUAUAGLU

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAA AGACGGAC GAA AUUCCAUG GAA AGUUCAAU GAA AUAGUUCA GAA ACAGAUAG GAA AGCUUUUC GAA ACAAGCUU GAA AGACAAGC GAA AAGACAAG GAA AUUTUAAGA GAA ACAAUUUA GAA AGUTUCAGU GAA AUCCCCAC GAA AGUCAAUC GAA AAGUCAAU GAA AUUCCCAG GAA AGGGUAUU GAA AAGGGUAU GAA AGAAGGGU GAA AAGAAGGG GAA AUG CULJCG GAA AUG CUGAU GAA AGUTUUCUU GAA ACAAGUUU GAA AGGUCUCG GAA ACUGGGUU GAA AUUUCUUC GAA AALUUCLU GAA AAAUUUCU GAA AAAAUUUC GAA AGGUGCUC

GUCCGUCUC

CAUGGAAUU

AUUGAACUA

UGAACUAUC

CUAUCUGUU

GAAAAGCUU

AAGCUUGUC

GCUUGUCUU

CUTUGUCUTUA

UCUUAAAUU

UAAAUUGUA

ACUGAACUA

GUGGGGAUU

GAUUGACUU

AUUGACUUC

CUGGGAAUA

AAUACCCUU

AUACCCUTUC

ACCCLTUCUU1 ccUTJCUUc

CGAAGCAUC

AUCAGCAUA

AAGAAACUU

AAACUUGUA

CGAGACCUA

AACCCAGUC

GAAGAAAUU

AAGAAAULU

AGAAAUUUU

GAAAUUUUU

GAGCACCUU

AUGGAAUU

GAACUAUC

UCUGUUGG

UGUUGGAG

GGAGAAAA

GUCUUAAA

UUAAAUUG

AAAUUGUA

AAUTUGUAC

GUACAGCA

CAGCAAGA

AAUGUGGG

GACUUCAA

CAACUGGG

AACUGGGA

CCCUUCUU

CUUCGAAG

UUCGAAGC

CGAAGCAU

GAAGCAUC

AGCAUAAG

AGAAACUUJ

GUAAACCG

AACCGAGA

AAAACCCA

UGGGAGUG

UUTUGAGCA

UUGAGCAC

UGAGCACC

GAGCACCU

AACUAUAG

870 UCUAUAGU CUGAUGA X GAA AAGGUGCU ACCUAAUUG AGCACC=A ACUAUAGA 102 874 ACCAUCUA CUGAUGA X GAA AGUUAAGG CCUtJAACUA UAGAUGGU

S

*5 a a S. a 5555*5

S

876 885 905 908 923 956 957 960 966 979 980 981 984 988 989 990 1007 1009 20 1038 1044 1055 1059 1063 1064 1080 1088 1090 1101 1107 1112 1117

ACACCAU

CUCCGGGI

AGGUGUA(

CACAGGUC

GCCCACUC

CCCUGACI

ACCCUGA(

UGGACCCt

UUUUCAUC

AGCAACAP

AAGCAACP

AAAGCAAC

CCAAAAGC

ACUUCCAA

CACUtJCCA

CCACUUCC

CCACCAGA

UUCCACCA

GGGAUUCU

UUCGCAGG

AACCAAGG

GGGUAACC

GGGUGGGU

GGGGUGGG

UACCAUUU

CAUUEJUUA

UCCAULUU

UCAAGGGG

UUGGACtJC

UGUGAUUG

AAUUGUGU

-CUGAUGA

J CUGAUGA C CUGAUGA 37 CUGAUGA 37 CUGAUGA

SCUGAUGA

:CUGAUGA

J CUGAUGA

;CUGAUGA

LCUGAUGA

LCUGAUGA

CUGAUGA

CUGAtJGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA CUGAUGA 3 CUGAUGA CUGAUGA CUGAUGA Y~ CUGAUGA y CUGAUGA x CUGAUGA X K GAA AUAGUUAA K GAA ACACCAUC K GAA AUCCUUGG C GAA ACAAUCCU C GAA AUG CUGCA C GAA AUGUGCUG I GAA AAUGUGCU .GAA ACAAAUGU GAA ACCCUGAC GAA AGGUUUU GAA AAGGUUUU GAA AAAGGULU GAA ACAAAAGG GAA AGCAACAA GAA AAGCAACA GAA AAAGCAAC GAA AUUCCAUG GAA AGAUIJCCA GAA ACACGCUC GAA AUUCUGAC GAA ACUTUCGCA GAA AGGUACUU GAA ACCAAGGU GAA AACCAAGG GAA AUtUUCUGG GAA ACCAUUUU GAA AUACCAUU GAA AUJECCAUU GAA AGGGGUAU GAA ACUCAAGG GAA AUUGGACU

UUAACUAU

GAUGGUGU

CCAAGGAU

AGGAUUGU

UGCAGCAU(

CAGCACAL71

AGCACAUUE

ACAUUUGUc

GUCAGGGUC

AAAAACCUL

AAAACCUUL

AAACCLUUL

CCUUUUGUU

UUGUtJGCUU

UGUUGCUUU

GUU7GCUUUU

CAUGGAAUC

UGGAAUCUC

GAGCGUGUC

GUCAGAAUC

UGCGAAGUA

AAGUACCUU

ACCUUGGU

CCUUGGUUA

CCAGAAAUA

AAAAUGGUA

AAUGGUAUA

AAUGGAAUA

AUACCCCUU

CCUUGAGUC

AGUCCAAUc A GAUGGUGU A~ ACCCGGAG U3 GUACACCU k. CACCUGUG 7 CAGUGGGC J UGUCAGGG J GUCAGGGu

AGGGUCCA

CAUGAAAA

JUUGUUGCU

JUGUUGCUU

TGUtJGCUUUJ fGCUUUtUGG

IUUGGAAGU

UGGAAGUG

GGAAGUGG

UCUGGUGG

UGGUGGAA

AGAAUCCC

CCUGCGAA

CCUUGGUU

GGUUACCC

ACCCACCC

CCCACCCC

AAAUGGUA

UAAAAAUG

AAAAUGGA

CCCCUUGA

GAGUCCAA

CAAUCACA

ACACAAUU

1125 CCCGCUUU CUGAUGA X GAA AUUGUGUG CACACAAUU AAAGCGGG 103 p.

p 0 p 4 a p a. 1126 1140 1149 1150 1180 1181 1188 1191 1194 1195 1201 1206 1207 1208 1233 1235 1237 1242 1247 20 1251 1263 1274 1276 1278 1281 1283 1285 1294 1295 1298 1304 1315 1330

CCCCGCUU

AUCGUCAG

ACUUCCAU

CACIJUCCA

GACAGUGU

UGACAGJG

GUAAGGAU

UUGGUAAG

GGAUTUGGU

GGGALUJGG

UGAAAUGG

UCCLTUUGA

CUCCUUUG

UCcCtUtJ

ACCAGAGA

CAACCAGA

CACAACCA

ACAUACAC

GUGGGACA

UGGGGUGG

LTUCUCACC

AGAUTJAGA

AGAGAUUtA

GGAGAGAU

ACAGGAGA

CCACAGGA

AUCCACAG

CUGGUAGG

ACUGGUAG

CGUACUGG

UGGUGCCG

CAGCGUUU

AUAGACCG

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CLJGAUGA

CtJGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAA AAUUGUGU GAA ACAUGCCC GAA AUCGUCAG GAA AAUCGUCA GAA AUUUCCUG GAA AAUUtJCCU GAA ACAGUGUA GAA AUGACAGU GAA AGGAUGAC GAA AAGGAUGA GAA AUTUGGUAA GAA AUGGGALU GAA AAUGGGAU GAA AAAUGGGA GAA ACCACAUG GAA AGACCACA GAA AGAGACCA GAA ACCAGAGA GAA ACACAACC GAA ACAUACAC GAA AUCUGGGG GAA AUUUCUCA GAA AGAUUUCU GAA AGAGAUU GAA AUUAGAGA GAA AGAUUAGA GAA AGAGAUTUA GAA AUCCACAG GAA AAUCCACA GAA AGGAAUCC GAA ACUGGUAG GAA AGUGGUGC GAA ACAUGUCA

ACACAAUUA

GGGCAUGUA

CUGACGAUU

UGACGAUUA

CAGGAAAUUI

AGGAAAUUA

UACACUGUC

ACUGUCAUC

GUCAUCCUU

UCAUCCUUIA

UTUACCAAUC

AAUCCCALU

AUCCCAULJU

UCCCAUTUUC

CAUGUGGUC

UGUJGGUCUC

UGGUCUCUC

UCUCUGGUU

GGUUGUGUA

GUGUAUGUC

CCCCAGAUU

UGAGAAAUC

AGAAAUCUC

AAAUCUCUA

UCUCUAAUC

UCUAAUCUC

UAAUCUCUC

CUGUGGAUU

UGUGGAUTUC

GGAUUTCCUA

CUACCAGUA

GCACCACUC

UGACAUGUA

AAGCGGGG

CUGACGAU

AUGGAAGU

UGGAAGUG

ACACUGUC

CACUGUCA

AUCCUUAC

CUJUACCAA

ACCAAUCC

CCAAUCCC

CCAUTUUCA

UCAAAGGA

CAAAGGAG

AAAGGAGA

UCUCUGGU

UCUGGLITJG

UGGUUGUG

GUGUAUGU

UGUCCCAC

CCACCCCA

GGUGAGAA

UCUAAUCU

UAAUCUCU

AUCUCUCC

UCUCCUGU

UCCUGUGG

CUGUGGAU

CCUACCAG

CUACCAGU

CCAGUACG

CGGCACCA

AAACGCUG

CGGUCUAU

104 1335 AUGGCAUA CUGAUGA X GAA ACCGUACA UGUACGGUC UAUGCCAU 4~ 4.

4 1337 1344 1345 1348 1357 1362 1370 1372 10 1379 1416 1418 1433 1438 1466 1467 1480 1485 1491 1492 1495 1501 1505 1506 1510 1512 1515 1536 1540 1545 1548 1549 4* 4

GAAUGGC

GGGGGAG(

CGGGGGAC

AUGCGGG(

GUGGAUGI

UACCAGUC

ACUGCC-AJ

CAACUGCC

cuuccUcc

GUCACUG.A

LUGUCACUJ

CACAAGGG

UTUCUUCAC

CUCCCUGG

CCUCCCUG

UEJUCAAUULJ

UtJAACUTUC UUtJUUAUtJ AttUUTJAU

UTJGAUUUU

AGCAAALU

UUAGAGCA

AUtJAGAGC LTUCAALTUtA

CCUCAAU

ULTUCCUUC

AGGGUACU

AACAAGGG

UGGAUAAC

GCUtJGGAU

CGCUTUGGA

CUGAUGA

3CUGAUGA 3CUGAUGA 7CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA.

CUGAUGA:

CUGAUGA;

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA CUGAUGA 3 CUGAUGA CGAA AGACCGUA C GAA AUGGCAUA IGAA AAUGGCAU GAA AGGAAUGG GAA AUGCGGGG GAA AUGUGAUG GAA ACCAGUGG *GAA AUACCAGU *GAA ACUGCCAA GAA ACAGCUUG GAA AGACAGCU GAA AUGGGUUU GAA AGGGUAUG GAA AGUCCUCC GAA AAGUCCUC GAA AUUUCCUC GAA AUtJUUALU GAA ACIJUCAAU GAA AACUUCAA GAA AUTUAACLU GAA AUUTUUUAU GAA AUUGAUUU GAA AAUTUGAUU GAA AGCAAAU GAA AGAGCAAA GAA AUUJAGAGC GAA ACAGUUUU GAA ACUUACAG GAA AGGGUACU GAA ACAAGGGU GAA AACAAGGG

UACGGUCUJ

UAUGCCAUEt

AUGCCAUUC

CCAUUCCUc

CCCCGCAUC

CAUCACAUC

CCACUGGUP

ACUGGUAUL

UTUGGCAGUUJ

CAAGCUGUC

AGCUGUCUC

AAACCCAUA

CAUACCCUU

GGAGGACUU

GAGGACUTUC

GAGGAAAUA

AAUAAAAUU

AUUGAAGJU

UUGAAGUUA

AAGUUAAUA

AUAAAAAUC

AAAUCAAUU

AAUCAAUUU

AALUUGCUC

UUUGCUCUA

GCUCUAAUU

AAAACUGIJA

CUGUAAGUA

AGUACCCUJI

ACCCUUGUU

CCCLUGUTUA

k~ UGCCAUUC I CCUCcc

:CUCCCCCG

7CCCCGCAU

ACAUCCAC

CACUGGUA

UUGGCAGU

IGGCAGUUG

GGAGGAAG

UCAGUGAC

AGUGACAA

CCCUUGUG

GUGAAGAA

CCAGGGAG

CAGGGAGG

AAAUUGAA

GAAGUTUAA

AAUAAAAA

AUAAAAAU

AAAAUCAA

AAUTUUGCU

UGCUCUAA

GCUCUAAU

UAAUUGAA

AUTUGAAGG

GAAGGAAA

AGUACCCU

CCCUUGUU

GUTUAUCCA

AUCCAAGC

UCCAAGCG

1551 GCCGCUUG CUGAUGA X GAA AUAACAAG CUUGUUAUC CAAGCGGC 105

S

1568 1573 1574 1577 1593 1602 1623 1625 1628 1629 1645 1653 1654 1657 1658 1697 1699 1700 1721 1723 1727 1728 1737 1745 1752 1765 1773 1787 1800 1801 1811 1816 1819

ACAAAGCT

UUUGUACI

AULUGUAC

CACAUUtJC ACUUUGtUt ccUcuccc

UGGAAGGAP

CGUGGAAG

UCACGUGG

GUCACGUG

AAUUUCAG

UGCAAAGU

UUGCAAAG

AGGLTJGCA

CAGGUUGC

ACCACAAA

GCACCACA

UGCACCAC

CAAACGUA

CUCAAACG

GGUUCUCA

AGGIJUCUC

UACCAUGU

CAAGCUUG

UGUGGGCC

GAUTJGGCA

CCCACAUG

GUGUGGGC

UUTCtUJGCA

GUUCUUGC

GAGUAUCC

CCAAAGAG

UUTJCCAAA

J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

TCUGAUGA

'CUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I C GAA ACACAUUU C GAA AGCUGACA [GAA AAGCUGAC GAA ACAAAGCU GAA ACCGCUUC GAA ACUUUGUU GAA AUCACCCU *GAA AGAUCACC GAA AGGAGAUC *GAA AAGGAGAU GAA ACCCCUGG GAA AUUUCAGG GAA AAUUUCAG GAA AGUAAUUU GAA AAGUAALU GAA ACACGCUC GAA AGACACGC GAA AAGACACG GAA AUCUGUCU GAA AGAUCUGU GAA ACGUAGAU GAA AACGUAGA GAA AGGUUCUC GAA ACCAUGUG GAA AGCUUGUA GAA AGGCUGUG GAA AUUGGCAG GAA ACUCUCCC GAA ACAGGUGU GAA AACAGGUG GAA AGUUCtJLG GAA AUCCAAGU GAA AGUAUCCA UGUCAGCLr.

GUCAGCUJL

AGCUUJGU;

GAAGCGGUC

AACAAAGUC

AGGGUGAUC

GGUGAUCUC

GAUCUCCUUI

AUCUCCUUC

CCAGGGGUC

CCUGAAAUU

CUGAAAUTUA

AAAUUACUU

AAUUACXtJ

GAGCGUGUC

GCGUGUCUU

CGUGUCUUU

AGACAGAUC

ACAGAUCUA

AUCUACGUU

UCUACGUUU

GAGAACCUC

CACAUGGUA

UACAAGCUU

CACAGCCUC

CUGCCAAUC

GGGAGAGUU

ACACCUGUU

CACCUGUUU

CAAGAACUU

ACUUGGAUA

UGGAUACUC

JUGUACAAA

J GUACAAAU

LCAAAUGUG

AACAAAGU

GGGAGAGG

*UCCUUCCA

*CLTUJCCACG

CCACGUGA

CACGUGAC

CUGAAAUU

ACUUUGCA

CUUUGCAA

UGCAACCU

GCAACCUG

UUUGUGGU

UGUGGUGC

GUGGUGCA

UACGUUTUG

CGUTUUGAG

UGAGAACC

GAGAACCU

ACAUGGUA

CAAGCUEJG

GGCCCACA

UGCCAAUC

CAUGUGGG

GCCCACAC

UGCAAGAA

GCAAGAAC

GGAUACUC

CUCUUTUGG

LTIUUGGAAA

AAAUGUGUC AGCUUUGU 106 1821 AAUUUCCA CUGAUGA X GAA AGAGUAUC GAUACUCUU UGGAAAUUE 4.aa 0* 4 4 a 4* 4a a 4 1822 1829 1844 1845 1847 1849 1852 1866 1867 1868 1872 1881 1882 15 1892 1895 1913 1917 1923 1927 1954 1962 1971' 1977 1980 2001 2020 2032 2034 2046 2052 2054 2066

CAAUUUCC

UGGCAUUC

UAUUAGAG

CUAUUAGA

UGCUAUUA

UGUGCUJAU

AUTUUGUGC

AUGAUCAA

CAUGAUCA

CCAUGAUC

AGCUCCAU

GCALUUCUU

UGCAUTUCU

CCUGCAAG

GGUCCUGC

GGCAGACA

GCAAGGCA

UCUUGAGC

CCUGUCUU

GACCACGC

AGCUGCCU

AGGACUGU

CGCUCUAG

ACACGCUC

UUUCCUGU

UGUCGUCU

UUCCCCAA

CUTJUCccc

GAGACUUC

GUGCAUGA

CCGUGCAU

GATUCCCA

CUGAUGA

CUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

GAA AAGAGUAU :GAA AUUUCCAA *GAA ACAUGGUG GAA AACAUGGU GAA AGAACAUG GAA AGAGAACA GAA AUUAGAGA GAA AUGUCAU GAA AAUGUCAUJ GAA AAAUGUCA GAA AUCAAAAU GAA AGCUCCAU GAA AAGCUCCA GAA AUG CAUUC GAA AGGAUGCA GAA AGUCUJCCU GAA ACAUAGUC GAA AGGCAGAC GAA AGCAAGGC GAA AUGUCUUU GAA ACCACGCA GAA AGCUGCCt7 GAA ACUGUGAG GAA AGGACUGU GAA AUCGUGGG GAA AUUCUCCA GAA ACUUGUCG GAA AUACUUGU GAA AUGCUUUC GAA ACTJUCGAU GAA AGACUUCG GAA AUG CCGUG

AUACUCUUUJ

UUTGGAAAUU

CACCAUGUU

ACCAUGUUC

CAUGUUCUC

UGUUCUCUA

UCUCUAAUA

AAUGACAUU

AUGACAUUU

UGACAUULU

AUUUUGAUC

AUGGAGCJUU

UGGAGCUUA

GAAUGCAUC

UGCAUCCULJ

AGGAGACUA

GACUAUGUC

GUCUGCCU1J

GCCUUGCUC

AAAGACAUtJ

UGCGUGGUC

AGGCAGCUC

CUCACAGUC

ACAGUCCUA

CCCACGAUC

UGGAGAAUC

CGACAAGUA

ACAAGUAUUt

GAAAGCAUC

AUCGAAGUC

CGAAGUCUC

CACGGCAUC

GGAAAUUG

GAAUGCCA

CUCUAAUA

UCUAAUAG

UAAUAGCA

AUAGCACA

GCACAAAU

UUGAUCAU

UGAUCAUG

GAUCAUGG

AUGGAGCU

AAGAAUGC

AGAAUGCA

CUUGCAGG

GCAGGACC

UGUCUGCC

UGCCUUGC

GCUCAAGA

AAGACAGG

GCGUGGUC

AGGCAGCU

ACAGUCCU

CUAGAGCG

GAGCGUGU

ACAGGAAA

AGACGACA

UTUGGGGAA

GGGGAAAG

GAAGUCUC

UCAUGCAC

AUGCACGG

UGGGAAUC

107 9*

S

S.

2074 2080 2088 2096 2097 2098 2104 2115 2118 10 2126 2133 2136 2138 2160 2164 2166 2196 2198 2220 20 2221 2223 2246 2247 2248 2249 2250 2253 2256 2282 2289 2292.

2293 2295

UGGAGGGG

GAUCUGUG

AACCACAU

UAUCUUUA

UUAUCUEU

AUEJAUCTU

GGUCUCAU

UCUUCUAC

GAGUCUUTC

CAAUGCCU

UUCAAUAC

UCCLTUCAA

CAUCCUtJC

CGGAUAGU

UCUGCGGA

ACUCUGCG

CAGGUGUA

GGCAGGUG

CAGCCAAG

ACAGCCAA

GCACAGCC

UUAUGA AA

AUUAUGAA

UAUUAUGA

CUAUUAUG

UCUAUULAU

CCUUCUAU

GCACCUUC

UGALTUUCC

AGAAUAAU

ACUAGAAU

UACUAGAA

CCUACUAG

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

S

S. S

S

'0 GAA AUUCCCAG GAA AGGGGGAU GAA AUCUGUGG GAA ACCACAUG GAA AACCACAU GAA AAACCACA GAA AUCLUJUAA GAA AGGGUCUC GAA ACAAGGGU GAA AGUCUUCU GAA AUGCCUGA GAA ACAAUGCC GAA AUACAAUG GAA AGGUUCCG GAA AGUGAGGU GAA AUAGUGAG GAA AGGCCUUC GAA AGAGGCCU GAA ACACUGCA GAA AACACUGC GAA AGAACACU GAA AUGCCUCC GAA AAUGCCUC GAA AAAUGCCU GAA AAAAUGCC GAA AAAAAUGC GAA AUGAAAAA- GAA AUTUAUGAA GAA AGUtJCGUC GAA AUUUCCAA GAA AUGAUTUUC GAA AAUGAUU GAA AUAAUGAU

CUGGGAAUC

ATJCCCCCUC

CCACAGAUC

CAUGUGGUUI

AtJGUGGtUU UGUGGUtTUA

UUAAAGAUA

GAGACCCUU

ACCCUUGUA

AGAAGACUC

UCAGGCAUU

GGCAUUGUA

CAUUGUAUJ

CGGAACCUC

ACCUCACUA

CUCACUAUC

GAAGGCCUC

AGGCCUCUA

UGCAGUGLU

GCAGUGUTUC

AGUGUUCUJ

GGAGGCAUU

GAGGCAUUU

AGGCAUUUU

GGCAUUUUU

GCAUUULTJUC

UUUUCAUA

UTUCAUAAUA

GACGAACUU

UUGGAAAUC

GAAAUCALU

AAAUCAUUA

AUCALTUALU

CCCCUCCA

CACAGAUC

AUGUGGUU

UAAAGAUA

AAAGAUAA

AAGAUAAU

AUGAGACC

GUAGAAGA

GAAGACUC

AGGCAUTUG

GUAUTUGAA

UUGAAGGA

GAAGGAUG

ACUAUCCG

UCCGCAGA

CGCAGAGU

UACACCUG

CACCUGCC

CUTUGGCUG

UUGGCUGU

GGCUGUGC

UUUCAUAA-

LUJCAUAAU

UCAUAAUA

CAUAAUAG

AUAAUAGA

AUAGAAGG

GAAGGUGC

GGAAAUCA

AUTUAUTUCU

AUUCUAGU

UTUCUAGUA

CUAGUAGG

108 .i.

2296 2298 2301 2316 2324 2325 2327 2328 2334 2337 2338 2340 2343 2346 2349 2352 2361 2362 2396 20 2399 2402 2406 2409 2416 2427 2432 2443 2458 2459 2480 2481 2502

GCCUACUI

GUGCCUA(

GTJCGUGCC

AACAUGGC

GCCAGAAC

AGCCAGAP

GUAGCCAG-

AGUAGCCA

ACAAGAAG

AUGACAAG

GAUGACAA

AUGAUGAC

AGGAUGAU

CCUAGGAU

GUCCCUAG

ACGGUCCC

GCCCGCUU

GGCCCGCU

UGGACAAG

CGAUGGAC

UGACGAUG

UCCAUGAC

GGAUCCAU

UUCAUCUG

UCCAAUGG

GUTUCAUCC

UCGUUCAC

GGCAUCAU

UGGCAUCA

CUCUGGGG

UCUCUGGG

GGCUUACC

k. CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

LCUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA2 CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA

K GAA AAUAAUGA K GAA AGAAUAAU -K GAA ACUAGAAU C GAA AUCACCGU C GAA ACAUGGCA C GAA AACAUGGC I GAA AGAACAUG I GAA AAGAACAU CGAA AGCCAGAA GAA AGUAGCCA GAA AAGUAGCC GAA AGAAGUAG GAA ACAAGAAG GAA AUGACAAG GAA AUGAUGAC GAA AGGAUGAU GAA ACGGUCCC GAA AACGGUCC GAA AGCCUGUC GAA AGUAGCCU GAA ACAAGUAG GAA AUGGACAA GAA ACGAUGGA GAA AUCCAUGA GAA AGUUCAUC GAA AUGGGAGU GAA AUGUUCAU GAA AGGCAGUC GAA AAGGCAGU GAA AUTUCCCAU GAA AAUUCCCA GAA AGGUUCAG UCAUTUAUtJ(

AUUAUTUCUZ

ALUUCUAGUI

ACGGUGAUTI

UGCCAUGU.

GCCAUGUUC

CAUGUUCM

AUGUtJUUC

UUCUGGCUA

UGGCUACUUJ

GGCUACUUC

CUACUUCUU

CUUCUTUGUC

CUUGUCAUC

GUCAUCAUC

AUCAUCCUA

GGGACCGUU

GGACCGUUA

GACAGGCUA

AGGCUACUUI

CUACUUGUC

UUGUCCAUC

UCCAUCGUC

UCAUGGAUC

GAUGAACUC

ACUCCCAUJ

AUGAACAUUJ

GACUGCCUJ

ACUGCCUA

AUGGGAAUU

UGGGAAUUC

CUGAACCUA

-UAGUAGGC

k GUAGOCAC

GGCACGAC

IGCCAUGUU

J CUTJCUGGC

UUCUGGCU

CUGGCUAC

UGGCUACU

CUUCUGU

CU7UGUCAU

UUTGUCAUC

GUCAUCAU

AUCAUCCU

AUCCUAGG

CUAGGGAC

GGGACCGU

AAGCGGGC

AGCGGGCC

CUUGUCCA

GUCCAUCG

CAUCGUCA

GUCAUGGA

AUGGAUCC

CAGAUGAA

CCAUUGGA

GGAUGAAC

GUGAACGA

AUGAUGCC

UGAUGCCA

CCC CAGAG

CCCAGAGA

GGUAAGCC

2506 AAGAGGCU CUGAUGA X GAA ACCUAGGU ACCUAGGUA AGCCUCUU z 109 2512 ACGGCCAA CUGAUGA X GAA AGGCUUAC GUAAGCCUC UUGGCCGU 9 9 9* 9* 9**e*9 2514 2528 2529 2541 2555 2556 2562 2578 10 2589 2595 2603 2632 2638 2640 2645 2652 2658 2661 20 2664 2665 2668 2670 2674 2680 2682 2691 2697 2698 2700 2710 2730

CCACGGCC

CTJUGGCCA

UCUUGGCC

UCUGCUUC

CAAUUCCA

UCAAUIJCC

GUCULIGUC

UGUCCUGC

UUGACUGC

AACAUUUTJ

cucUuJc

GAGAGCUC

AGACAUGA

UCAGACAU

UGAGUUCA

AGGAUCUU

UGAAUGAG

AUAUGA.AU

CCAAUAUG.

ACCAAUAU

GUGACCAA

UGGUGACC

GAGAUGGU

CACAUUGA

ACCACAUU

AGAAGGUU

GCACCUAG

GGCACCUA

CAGGCACC

UGGCUUGG

AUCACCAU

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAA AGAGGCUU GAA AGOCACCA GAA AAGGCACC GAA AUCUCUUG GAA AGGCAUCU GAA AAGGCAUC GAA AUUCCAAA GAA AGUUGCUG GAA ACUGUCCU GAA ACUGCUAC GAA ACAUU2UUG GAA AUGCUCAC GAA AGCUCGAU GAA AGAGCUCG GAA ACAUGAGA' GAA AGUUCAGA GAA AUCtJUGAG GAA AGGAUCUU GAA AUGAGGAU GAA AAUGAGGA GAA AUGAAUGA GAA AUAUGAAU GAA ACCAAUAU GAA AUGGUGAC GAA AGAUGGUG GAA ACCACAUU GAA AGGUUGAC GAA AAGGLUJGA GAA AGAAGGUU GAA ACAGGCAC GAA AGUGGCCC

AAGCCUCUU

UGGUGCCUJ

GGUGCCULU

CAAGAGAUU

AGAUGCCUU

GAUGCCUUU

UUJUGGAAUU

CAGCAACUU

AGGACAGUA

GUAGCAGUC

CAAAAUGUU

GUGAGCAUC

AUCGAGCUC

CGAGCUCUC

UCUCAUGUC

UCUGAACUC

CUCAAGAUC

AAGAUCCUC

AUCCUCAUU

UCCUCAUUC

UCAUUCAUA

AUUCAUAUU

AUAUUGGUC

GUCACCAUC

CACCAUCUC

AAUGUGGUC

GUCAACCUU

UCAACCUUC

AACCUUCUA

GUGCCUGUA

GGGCCACUC

GGCCGUGG

UGGCCAAG

GGCCAAGA

GAAGCAGA

UGGAAUUG

GGAAUUGA

GACAAGAC

GCAGGACA

GCAGUCAA

AAAAUGUU

GAAAGAAG

GAGCUCUC

UCAUGUCU

AUGUCUGA

UGAACUCA

AAGAUCCU

CUCAUUCA

AUUCAUAU

CAUAUUGG

AUAUUGGU

UUGGUCAC

GGUCACCA

ACCAUCUC

UCAAUGUG

AAUGUGGU

AACCUUCU

CUAGGUGC

UAGGUGCC

GGUGCCUG

CCA:AGCCA

AUGGUGAU

2739 AAUUCCAC CUGAUGA X GAA AUCACCAU AGUAUGGAU AUGGUGAL71J GUGGAALTU 110 a.

a a a.

a a a. a a 2747 2748 2756 2757 2768 2773 2774 2798 2799 2802 2807 2828 2829 2833 15 2846 2850 2859 2869 2882 20 2892 2899 2909 2918 2924 2925 2939 2943 2952 2968 2977 2981 2983

AUUUGCAC

AAUUUGC.P

GGUUUCCP

AGGUUUClC

GGUAAGUG

CCUCAGGU

UCCUCAGG

AGGGGACA

UAGGGGAC

UUGUAGGG

UGGUCUUG

CUUGACGG

CCUUGACG

tutJcccuu

CUCCAACG

AUUGCUCC

UCCACAGG

CCGUUUCA

UGCUGUCC

CUACUGGU

GCUCUGGC

AGCUGGCU

CAAAUCCA

CCUCCACA

UCCUCCAC

CACUGAGG

ACAUCACU

UCUUCU71c

AUCUUCAG

CUEJAUACA

AGUCCUTUA

GAAGUCCU

;CUGAUGA

LCUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

.CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

*GAA AUUCCACA GAA AAUUCCAC *GAA AUUUGCAG GAA AAUUUGCA GAA ACAGGUUU GAA AGUGGACA GAA AAGUGGAC GAA AUUtCAUUU GAA AAUTUCAUU GAA ACAAAUJC GAA AGGGGACA GAA AUCGUGCC GAA AAUCGUGC GAA ACGGAAUC GAA AGUCUUUC GAA ACGUAGUC GAA AUJUGCUCC GAA AUCCACAG GAA AGCGCCGU GAA AUGCUGUC GAA ACUGGUGA GAA AGCUCUGG GAA AGCUGGCU GAA AUCCAGAG GAA AAUCCAGA GAA ACUUCUCC GAA AGGGACUU GAA ACAUCACU GAA AGCUUCCU GAA AUCUTUCAG GAA ACAGAUCU GAA AUACAGAU

UGUGGAAUUJ

GUGGAAUUC

CUGCAAAUU

UGCAAAUUU

AAACCUGUC

UGUCCACUU

GUCCACUUA

AAAUGAAUU

AAUGAAUUU

GAAUUUGUC

UGUCCCCUA

GGCACGAIU

GCACGAUUC

GAUUCCGUC

GAAAGACUA

GACUACGUU

GGAGCAAUC

CUGUGGAUC

ACGGCGCUU

GACAGCAUC

UJCACCAGUA

CCAGAGCUC

AGCCAGCUC

CUCUGGALU

UCUGGAUUU

GGAGAAGUC

AAGUCCCUC

AGUGAUGUA

AGGAAGCUC

CUGAAGAUC

AGAUCUGUA

AUCUGUAUA

CUGCAAAU

UGCAAAUU

UGGAAACC

GGAAACCU

CACUUACC

ACCUGAGG

CCUGAGGA

UGUCCCCU

GUCCCCUA

CCCUACAA

CAAGACCA

CCGUCAAG

CGUCAAGG

AAGGGAAA

CGUUGGAG

GGAGCAAU

CCUGUGGA

UGAAACGG

GGACAGCA

ACCAGUAG

GCCAGAGC

AGCCAGCU

UGGAUTUUG

UGUGGAGG

GUGGAGGA

CCUCAGUG

AGUGAUGU

GAAGAAGA

CUGAAGAU

UGUAUAAG

UAAbGACU

AGGACUUC

2990 AGGUCAGG CUGAUGA X GAA AGUCCUUA UAAGGACUUT CCUGACCU

A-

0 a..a 00 0 0 a 0a a...0 2991 2999 3007 3009 3012 3016 3017 3023 3024 3034 3047 3048 3050 3056 3067 3069 3094 3096 3099 3101 3102 3104 3120 3121 3126 3134 3135 3140 3151 3153 3154 3155 3157 AAGGUCAG CUGAUGA X GAA AAGUCCUU GAUGCUCC CUGAUGA X GAA AGGUCAGG ACAGAUGA CUGAUGA X GAA AUGCUCCA UAACAGAU CUGAUGA X GAA AGAUGCUC CUGUAACA CUGAUGA X GAA AUGAGAUG GAAGCUGU CUGAUGA X GAA ACAGAUGA GGAAGCUG CUGAUGA X GAA AACAGAUG CCACUUGG CUGAUGA X GAA AGCUGUAA GCCACUUG CUGAUGA X GAA AAGCUGUA CAUGCCCU CUGAUGA X GAA AGCCACUU AUGCCAAG CUGAUGA X GAA ACUCCAUG GAUGCCAA CUGAUGA X GAA AACUCCAU GCGAUGCC CUGAUGA X GAA AGAACUCC ACUUUCGC CUGAUGA X GAA AUGCCAAG CCUGUGGA CUGAUGA X GAA ACACUUtJC UCCCUGUG CUGAUGA X GAA AUACACUU UAAGAGGA CUGAUGA X GAA ALTTUJCGUG GAUAAGAG CUGAUGA X GAA AUAUUUCG UCCGAUAA CUGAUGA X GAA AGGAUAUU UCUCCGAU CUGAUGA X GAA AGAGGAUA UUCUCCGA CUGAUGA X GAA AAGAGGAU UCUUCUCC CUGAUGA X GAA AIJAAGAGG CAGAUU!JU CUGAUGA X GAA ACCACGULJ ACAGAUUU CUGAUGA X GAA AACCACGU AAGUCACA CUGAUGA X GAA AUUUUtAAC CC.AAGCCA CUGAUGA X GAA AGUCACAG GCCAAGCC CUGAUGA X GAA AAGUCACA CCCGGGCC CUGAUGA X GAA AGCCAAAG UUUAUAAA CUGAUGA X GAA AUCCCGGG UCUUUAUA CUGAUGA X GAA AUAUCCCG AUCUUUAU CUGAUGA X GAA AAUAUCCC GAUCUTUUA CUGAUGA X GAA AAAUAUCC UGGAUCUU CUGAUGA X GAA AUAAAUAU AAGGACUUC CUGACCUU.

CCUGACCUU GGAGCAUC UGGAGCAUC UCAUCUGU GAGCAUCUC AUCUGUJEA CAUCUCAUC UGUUACAG UCAUCUGUU ACAGCUUC CAUCUGUUA CAGCUUCC UUACAGCUU CCAAGUGG UACAGCUUC CAAGUGGC AAGUGGCUA AGGGCAUG CAUGGAGJU CUtJGGCAU AUGGAGUUC UUGGCAUC GGAGUTUCUU GGCAUCGC CULJGGCAUC GCGAAAGU GAAAGUGUA UCCACAGG AAGUGUAUC CACAGGGA CACGAAAUA UCCUCULJA CGAAAUAUC CUCULJAUC AAUAUCCUC UTUAUCGGA UAUCCUCUU AUCGGAGA AUCCUCUEJA UCGGAGAA CCUCLTUAUC GGAGAAGA AACGUGGUU AAAAUCUG ACGUGGUtJA AAAUCUGU GUUAAAAUC UGUGACUU CUGUGACUU UGGCUUGG UGUGACUUU GGCUUGGC CUTUUGGCUtJ GGCCCGGG CCCGGGAUA UUUAUAAA CGGGAUAUU UAUAAAGA GGGAUAUUU AUAAAGAU GGAUAUTUUA UAAAGAUC AUAUUUAUA AAGAUCCA 112 3163 AUAAUCUG CUGAUGA X GAA

S

55555. 0

S

5 3169 3170 3174 3190 3195 3199 3200 3225 3226 3227 3228 3239 3246 15 3258 3263 3265 3266 3267 20 3273 3274 3275 3288 3290 3291 3292 3293 3296 3297 3304 3305 3307 3311

UCUGACAU

UUCUGACA

cuuuUCU

AGGGAGGC

UUCAAAGG

CCAUUUJCA

UCCAUUUC

CUGUCAAA

UCUGUCAA

CUCUGUCA

ACUCUGUC

GGAUTUGUG

UCACUCUG

AAAGACCA

CACCAAAA

AACACCAA

AAACACCA

AAAACACC

CACAGCAA

CCACAGCA

CCCACAGC

AAGGAAAA

CUAAGGAA

CCUAAGGA

ACCUAAGG

CACCUAAG

AAGCACCU

GAAGCACC

AUAUGGAG

GAUAUGGA

AGGAUAUG

CCCCAGGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

AUCUUIJAU

AUCUGGAU

AAUCUGGA

ACAUAAUC

AGCAUCUC

AGGCGAGC

AGGGAGGC

AAGGGAGG

AUUGUUTUC

AAUTUGUUU

AAAUUGLTI

AAAAUUGU

ACACUCUG

AUUGUGUA

ACGUCACU

ACCAGACG

AGACCAGA

AAGACCAG

AAAGACCA

ACACCAAA

AACACCAA

AAACACCA

AUTUUCCCA

AUAUtJUCC

AAUAUUUC

AAAUAUUU

AAAAUALU

AGGAAAAU

AAGGAAAA

AGCACCUA

AAGCACCU

AGAAGCAC

AUGGAGAA

AUAAAGAUC CAGAUUAU.

AUCCAGAUU AUGUCAGA UCCAGAUUA UGUCAGAA GAUUAUGUC AGAAAAGG GAGAUGCUC GCCUCCCU GCUCGCCUC CCUUUGAA GCCUCCCUU UGAAAUGG CCUCCCUUU GAAAUGGA GAAACAAUIJ LUJUGACAG AAACAAUTLU UtJGACAGA AACAAULUUJ UGACAGAG ACAAUUUUU GACAGAGU CAGAGUGUA CACAAUCC UACACAAUC CAGAGUGA AGUGACGUC UGGUCUUU CGUCUGGUC UUUUGGUG UCUGGUCUU UUGGUGU CUGGUCUTUU UGGUGUUU UGGUCUUUU GGUGUUUU UTUUGGUGULJ UTUGCUGUG UUGGUGUTUU UGCUGUGG UGGUGUUUU GCUGUGGG UGGGAAAUA UUUtJCCUU GGAAAUAUU UUCCUUAG GAAAUALUUJ UCCUIJAGG' AAAUALUUUJ CCUUAGGU.

AAUAULUJUC CUUAGGUG AUUUUCCUU AGGUGCUU UUUUCCUUA GGUGCUUC UAGGUGCUU CUCCAUAU AGGUGCUUC UCCAUAUC GUGCUTUCUC CAUAUCCU UUCUCCAUA UCCUGGGG a- 113 a 9* .00:: boo a* 3313 3321 3327 3338 3339 3340 3343 3350 3364 3382 3383 3385 3388 3401 3439 3452 3453 3454 3455 3461 3472 3473 3481 3483 3485 3493 3499 3518 3522 3525 3526 3528

UACCCCAG

UCAAUCU

UCUTUCAUC

GCCUACAA

CGCCUACA

UCGCCUAC

CAAUCGCC

cTUCUUC

CCUCAUUC

UGUAGUAU

GTJGUAGUA

UGGUGUAG

UUCUGGUG

UGGUCUGG

GGGUCUCU

ACUCUGAA

AACUCUGA

CAACUCUG

CCAACUCU

GUUCCACC

AUTUUCCCA

GAUUUCCC

UUGCAAGA

GCUUGCAA

UAGCUUGC

CUGAGCAU

AUCCUGCU

GAACAAUG

GGAAGAAC

AUCGGAAG

UAUCGGAA

GAUAUCGG

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CTJGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAA AUAUGGAG GAA ACCCCAGG GAA AUCUUUAC GAA AUUCUTUCA GAA AAUUCUUC GAA AAAUUCUU GAA ACAAAALU GAA AUCGCCUA GAA AGUUCCUUr GAA AUCAGGG GAA AAUCAGGG GAA AUAAUCAG GAA AGUAUAAU GAA ACAUUUCU GAA ACUGGGCU

GAA'ACGUGGGU

GAA AACGUGGG GAA AAACGUGG GAA AAAACGUG GAA ACUCUGAA GAA AUGUUCCA GAA AAUGUTUCC GAA AUUUCCCA GAA AGAUUUCC GAA AGAGAUUU GAA AGCUUGCA GAA AGCAUUAG GAA AGUCLTUG GAA AUGUAGUC GAA ACAAUGUA GAA AACAAUGU GAA AGAACAAU

CCUGGGGUA

GUAAAGAUU

UGAAGAAUU

GAAGAAUUU

AAGAAUUUU

AAUtJUUGUA

UAGGCGAUU

AAGGAACUA

CCCCUGAUU

CCCUGAUUA

CUGAUTUAUA

AUUAUACUA

AGAAAUGUA

AGCCCAGUC

ACCCACGUU

CCCACGUUU

CCACGUUUUJ

CACGUUEJUC

UUCAGAGUU

UGGAACAUU

GGAACAUUU

UGGGAAAUC

GGAAAUCUC

AAAUCUCUU

UGCAAGCUA

CUAAUGCUC

CAAAGACUA

GACUACAUU

UACAUTUGU

ACAUUTGUUC

AUUGUUCUU

AAGAUUGA

GAUGAAGA

UUGUAGGC

UGUAGGCG

GUAGGCGA

GGCGAUUG

GAAAGAAG

GAAUGAGG

AUACUACA

UACUACAC

CUACACCA

CACCAGAA

CCAGACCA

AGAGACCC

UUJCAGAGU

UCAGAGUU

CAGAGUUG

AGAGUUGG

GGUGGAAC

UGGGAAAU

GGGAAAUC

UCUUGCAA

UEJGCAAGC

GCAAGCUA

AUGCUCAG

AGCAGGAU

CAUUGUUC

GUUCUUCC

CUUCCGAU

UUCCGAUA

CCGAUAUC

CUCCAUAUC CUGGGGUA 3529 UGAUAUCG CUGAUGA X GAA AAGAACAA UGUUCCAAC LTUGLTUCLTUC CGAUAUCA 114 00 *0 0 0000 000000 0 00 0 0 0000 00 0 0 0000 00 0 0 000 0000 00.

0 0~00 0000 0* 00 0 @000 0 0000 0 £00006, 0 0 000000 0 3534 3536 3544 3545 3562 3563 3570 3572 3574 10 3580 3584 3591 3592 3593 15 3598 3615 3629 3630 3634 20 3635 3654 3658 3662 3664 3676 3702 3710 3711 3718 3720 3725 3726 3741

GUCUCUGA

AAGUCUCU

CAUGCUCA

CCAUGCUC

GAGUCCAG

AGAGUCCA

GGCAGAGA

UAGGCAGA

GGUAGGCA

AGGUGAGG

AAACAGGU

AUACAGGA

CAUACAGG

CCAUACAG

CUCCUCCA

GGGUCACA

CAUAAUGG

UCAUAAUG

GUUGUCAU

UGUUGUCA

UACUGACU

CAGAUACU

UCUGCAGA

GUUCUGCA

CUUUCGCU

AAUGUUUU

UAUCUUCA

AUAUCUUC

UAACGGGA

UCUAACGG

GUUCUJCU

GGTJUCUUC

AUUACUUU

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

GAA AUCGGAAG GAA AUAUCGGA GAA AGUCUCUG GAA AAGUCUCU GAA AUCCUCUU GAA AAUCCUCU GAA AGUCCAGA GAA AGAGUCCA GAA AGAGAGUC GAA AGOCAGAG GAA AGGUAGGC GAA ACAGGUGA GAA AACAGGUG GAA AAACAGGU GAA ACAGGAAA GAA ACUUCCUC GAA AUUUGGGG GAA AAUUUGGG GAA AUGGAALU GAA AAUGGAAU GAA AUUCCUGC GAA ACUGAUUC GAA ACUGACUG GAA AUACUGAC GAA ACUGUUCU GAA ACACUCAC GAA AUGUUJTJU GAA AAUGUUU(J GAA AUCUUCAA GAA AUAUCUUC GAA ACGGGAUA GAA AACGGGAU GAA ACUUCUGG

CUUCCGAUA

UCCGAUAUC

CAGAGACUU

AGAGACLUU

AAGAGGAUU

AGAGGAUUC

UCtJGGACUC

UGGACUCUC

GACUCUCUC

CUCUGCCUA

GCCUACCUC

UCACCUGUU

CACCUGUUU

ACCUGUUUC

LUJUCCUGUA

GAGGAAGUA

CCCCAAAUU

CCCAAAUUC

AAUUCCAUU

AUUCCAUUA

GCAGGAAUC

GAAUCAGUC

CAGUCAGUA

GUCAGUAUC

AGAACAGUA

GUGAGUGUA

AAAAACAUU

AAAACALUU

UUGAAGAUA

GAAGAUAUC

UAUCCCGUU

AUCCCGUUA

CCAGAAGUA

UCAGAGAC

AGAGACUU

UGAGCAUG

GAGCAUGG

CUGGACUC

UGGACUCU

UCUCUGCC

UCUGCCUA

UGCCUACC

CCUCACCU

ACCUGUUU

UCCUGUAU

CCUGUAUG

CUGUAUGG

UGGAGGAG

UGUGACCC

CCAUTUAUG

CAUUAUGA

AUGACAAC

UGACAACA

AGUCAGUA

AGUAUCUG

UCUGCAGA

UGCAGAAC

AGCGAAAG

AAAACALU

UGAAGAUA

GAAGAUAU

UCCCGUUEA

CCGUTUAGA

AGAAGAAC

GAAGAACC

AAAGUAAU

115 3747 3750 3778 3783 3784 3786 3791 3808 3809 3827 3828 3830 3832 3836 15 3838 3839 3840 3872 3881 3890 3908 3914 3920 3922 3926 3950 3953 3972 3973 3974 3975 3984 3990

UCUGGGAU

UCAUCUGG

AAGAACCA

GAGGCAAG

UGAGGCAA

UCUGAGGC

GCUCUUCU

GUCUUCCA

UGUCUUCC

AUGGAGAU

GAUGGAGA

AAGAUGGA

AAAAGAUG

CACCAAAA

UCCACCAA

UUCCACCA

AULJCCACC

AUGCCACA

AGCCUTUCA

UCUGGUUU

CGGACUGG

GAUAUCCG

CGGAGUGA

AUCGGAGU

UGUCAUCG

CACUGGAG

CCUCACUG

AGCUUUAA

CAGCUUTUA

UCAGCUUIJ

AUCAGCU-

CCAAUCUC

UGCACUCC

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CTJGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA.

CUGAUGA

CUGAUGA:

GAA ACUUUUAC GAA AUTUACt.UU GAA ACCACUGU GAA ACCAUACC GAA AACCAUAC GAA AGAACCAU GAA AGGCAAGA GAA AGUUUUCA GAA AAGUUUUC GAA AUUUGGUU GAA AAUUIJGGU GAA AUAAUUUG GAA AGAUAAUU GAA AUGGAGAU GAA AGAUGGAG GAA AAGAUGGA GAA AAAGAUGG GAA ACUCCCUG GAA AUGCCACA GAA AGCCUUCA GAA AGCCGCUU GAA ACUGGUAG GAA AUCCGGAC GAA AUAUCCGG GAA AGUGAUAU GAA ACACGGUG GAA AGUACACG GAA AGUUCUGC GAA AAGUUCUG GAA AAAGUTJCU GAA AAAAGUUC GAA AUCAGCUU GAA AUCUCUAU

GUAAAAGUA

AAAGUAAUC

ACAGUGGUA

GGUAUGGUU

GUAUGGUUC

AUGGUUCUtJ

UCUUGCCUC

UGAAAACUU

GAAAACUU

AACCAAAUU

ACCAAAUUA

CAAAUUAUC

AAUUAUCUC

AUCUCCAUC

CUCCAUCUIJ

UCjCAUCUUU

CCAUCUTUUU

CAGGGAGUC

UGUGGCAUC

UGAAGGCUC

AAGCGGCUA

CUACCAGUC

GUCCGGAUA

CCGGAUAUC

AUAUCACUC

CACCGUGUA

CGUGUACUC

GCAGAACUU

CAGAACUULJ

AGAACUUU

GAACUUUUA

AAGCUGAUA

AUAGAGAUU

AUCCCAGA

CCAGAUGA

UGGtTTJCUU

CUEJGCCUC

UUGCCUCA

GCCUCAGA

AGAAGAGC

UGGAAGAC

GGAAGACA

AUCtJCCAU

UCUCCAUC

UCCAUCUU

CAUCUUUU

UUUEJGGUG

LJUGGUGGA

UGGUGGAA

GGUGGAAU

UGUGGCAU

UGAAGGCU

AAACCAGA

CCAGUCCG

CGGAUAUC

UCACUCCG

ACUCCGAU

CGAUGACA

CUCCAGUG

CAGUGAGG

UTUAAAGCU

UAAAGCUG

AAAGCUGA

AAGCUGAU

GAGAUTUGG

GGAGUGCA

116 4* 4006 4020 4021 4023 4052 4054 4057 4062 4063 10 4064 4076 4089 4098 4110 15 4115 4120 4121 4122 4130 20 4133 4134 4136 4137 4138 4153 4161 4162 4166 4167 4168 4169 4172

GGCTJGUGC

GGCUGGAC

AGGCUG.

UCAGGCUG

CAGGAGGA

AACAGGAG

UTJAAACAG

UCCUUUUA

UtJCCUULTrJ

CUTUCCUUU

GGGGUGUG

AUGUCCGG

UCUCAUGU

UCUGAGCA

CAAAAUCU

CACUUCAA

ACACUUCA

AACACUUC

GAAAGAAC

GUGGAAAG

GGUGGAAA

CUGGUGGA

GCUGGUGG

UGCUGGUG

AAUGCGGC

GAAAAUCA

UGAAAAUC

GAAAUGAA

CGAAAUGA

UCGAAAUG

GUCGAAAU

GUTUGUCGA

'CUGAUGA

;CUGAUGA

CUGAUGA

CUGAUGA

*CUGAUGA

*CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGYA

CUGAUGAI

CUGAUGA I CUGAUGA I CUGAUGA 2 CUGAUGA CUGAUGA GAA ACCGGULU GAA AUCUGGGC *GAA AAUCUGGG *GAA AGAAUCUG *GAA AGCUCAGU GAA AGAGCUCA GAA AGGAGAGC GAA ACAGGAGG GAA AACAGGAG GAA AAACAGGA GAA AUGCUJCC GAA AGUtJGGGG GAA AUGUCCGG GAA ACCUCUCA GAA AGCAGACC GAA AUCUGAGC GAA AAUCUGAG GAA AAAUCUGA GAA ACACUUCA GAA ACAACACU GAA AACAACAC GAA AGAACAAC GAA AAGAACAA GAA AAAGAACA GAA ACUUCCUG GAA AUGCGGCU GAA AAUGCGGC GAA AUCAAAUG GAA AAUCAAAU GAA AAAUCAAA GAA AAAAUCAA GAA AUGAAAAU

.AAACCGGLZ

GCCCAGALTL

CCCAGAUTUC

CAGAUUCUC

ACUGAGCUC

UGAGCUCUC

GCUCUCCUC

CCUCCUGUU

CUCCUGLUU

UCCUGUUtJA

GGAAGCAUC

CCCCAACUC

CCGGACAUC

UGAGAGGUC

GGUCUGCUC

GCUCAGAUUI

CUCAGAUUU

UCAGAUUJU

UGAAGUGUU

AGUGUUGUU

GUGUUGtJUC

GUUGUTUCUU

UTUGUUCUJU

UGUUCUUUC

CAGGAAGUA

AGCCGCAUU

GCCGCAUULJ

CAUUUGAUU

AUUUGAUUU

UUJUGAUUUU

UUGAUUUUC

AUUUUCAUU

SGCACAGCC

ICUCCAGCC

UCCAGCCU

CAGCCUGA

UCCUCCUG

CUCCUGUJ

MUGTUUAA

UAAAAGGA

AAAAGGAA

AAAGGAAG

CACACCCC

CCGGACAU

ACAUGAGA

UGCUCAGA

AGAUUUUG

UTUGAAGUG

UGAAGUGU

GAAGUGUU

GUUCUUUC

CULTUCCAC

UUIJCCACC

UCCACCAG

CCACCAGC

CACCAGCA

GCCGCAUU

UGAUUUTUC

GAUUUUCA

UUCAtJLTUC

UCAUTUUCG

CAUUUCGA

AUUUCGAC

UCGACAAC

4173 UGUUGUCG CUGAUGA X GAA AAUGAAAA UUCUUCAAC UUUUCAUUU CGACAACA 117 4174 4194 4214 4216 4217 4219 CUGUUGUC CUGAUGA X GAA AAAUGAAA UGCAGUCC CUGAUGA X GAA AGGUCCUU GCCUAGAA CUGAUGA X GAA AGCUGGCU AAGCCUAG CUGAUGA X GAA AGAGCUGG CAAGCCUA CUGAUGA X GAA AAGAGCUG CACAAGCC CUGAUGA X GAA AGAAGAGC UUUCAUUUC GACAACAG AAGGACCUC GGACUGCA AGCCAGCUC UUtCUAGGC CCAGCUCUU CUAGGCUU CAGCUCUUC UAGGCUUG GCUCUUCUA GGCUUGUG Where "IX" represents stern II region of a HH ribozyme (Hertel et al., 1992 Nucleic Acids Res. 20 3252). The length of stern II may be a 2 base-pairs.

C. e* 6.

S

S S 0 118 Table V: Human KDR VEGF Receptor-Hairpin Ribozvme and Substrate Secruences nt.

Position Hairpin Ribozyme Sequence Substrate 11 18 51 86 318 358 510 623 683 705 833 932 1142 1259 1332

CGACGGCC

CACAGGGC

CCCACAGA

UGAGCCUG

GAGGCCAA

AAAUGGAG

CUGUUACC

ACAUAAUA

UIJCCAUGA

TUIJUCUCC

CACUCCCA

UCUUGGUC

CCAUAAUC

UCUCACCA

AUGGCAUA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCACCU

GCCAGC

GCCCGG

GAUCAA

GtJUUCC

GUAAUC

GGAACA

GGUAAC

GACUCA

GAUAGU

GGGIUU

GCCCAC

GUACAU

GGGGUG

GUACAU

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA.

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAKGAAACACACGUUGUGGUACAUrJACCUGGUA ACCAGAGAAACACACGUUGUGGUACAUUrACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUrJACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUrACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAACACACGUJGUGGUACAUUTACCUGGUA

AGGUGCU

GCUGGCC

CCGGGCC

UUGAUCU

GGAAACU

GATJUACA

UGUUCCU

GUUACCA

UGAGUCC

ACUAUCU

AAACCCA

GUGGGCU

AUGUACU

CACCCCA

AUGUACG

GCU

GUC

CC

CC

GAC

GAU

GAU

GUC

GUC

GU)

GUC

CA)

GAC

GA)

GUC

GGCCGUCG

GCCCUGUG

UCT)GUGGG

CAGGCUCA

T)UGGCCUC

CUCCAUUU

GGUAACAG

CO

UAT)TAUGU

UCAT)GGAA

GGAGAAAA

UGGGAGUG

GACCAAGA

GATUIAUGG

UGGUGAGA

UAUGCCAU

119 1376 CUUCCUCC AGAA GCCAAU ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA AUUGGCA GUIJ GGAGGAAG 1413 1569 1673 1717 1760 1797 1918 1967 1974 2021 2084 2418 2453 2492 2547 2765 2914 2993

GUCACUGA

UUGUACAA

GCUCAGUG

AAACGUAG

UUTGGCAGA

UUCUIJGCA

UUGAGCAA

GGACUGUG

CGCUCUAG

UACUUGUC

ACCACAUG

GGGAGUUC

CAUCAUAA

CUAGGUUC

CCAAAGGC

GGUAAGUG

AAAUCCAG

GCUCCAAG

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCUUGG ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GACACA ACCAGAGAAACACACGIJUGUGGUACAUUACCUGGUA GCAUGU ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GUCUGC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GUGGGC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GGUGUG ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GACAUA ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GCCUGA ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GUGAGC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GAUUCU ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GUGGAG ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GGAUCC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GUCGUU ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA GGUCUC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GCUUCA ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA GGUUUC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GGCUGA ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GGAAGU ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

CCAAGCU

UGUGUCA

ACAUGCA

GCAGACA

GCCCACA

CACACCU

UAUGUCU

UCAGGCA

GCUCACA

AGAAUCA

CUCCACA

GGAUCCA

AACGACU

GAGACCG

UGAAGCA

GAAACCU

UCAGCCA

ACUUCCU

GUC

GCU

GCC

GAU

GCC

GIUU

GCC

GCU

GUC

GAC

GAU

GAU

GCC

GCU

GAU

GUC

GCU

GAC

UCAGUGAC

UUGUACAA

CACUGAGC

CUACGUUU

UCUGCCAA

UGCAAGAA

UIJGCUCAA

CACAGUCC_

CUAGAGCG

GACAAGUA

CAUGUGGU

GAACUCCC

UUAUGAUG

GAACCUAG

GCCUUUGG

CACUUACC

CUGGAUUU

CLTUGGAGC

120 3019 3165 3378 3404 3418 3575 3588 3689 3753 3764 3911 3927 4011 4016 4025 4059 4111 4116 4195

CACUUGGA

CUGACAUA

GUAGUAUA

CCAGCAUG

CCCGUGCC

GUGAGGUA

AUACAGGA

CACUCACA

UGGUUGUC

CACUGUCC

GAUAUCCG

UCUGUGUC

AGAAUCUG

GCUGGAGA

CCGUGUCA

UCCUUJUUA

AAAAUCUG

ACUUCAAA

UCCCUGCA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GUAACA

GGAUCU

GGGGCC

GGUACA

GUCCAG

GAGAGA

GGUGAG

GGCUCU

GGGAUU

GGUUGU

GGUAGC

GAGUGA

GUGCUA

GGGCUG

GGAGAA

GGAGGA

GACCUC

GAGCAG

GAGGUC

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUrGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGIJUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

UGUUACA

AGAUCCA

GGCCCCU

UGUACCA

CUGGACU

UcUCUCU

CUCACCU

AGAGCCG

AAUCCCA

ACAACCA

GCUACCA

UCACUCC

UAGCACA

CAGCCCA

IJUCUCCA

UCCUCCU

GAGGUCU

CUGCUCA

GACCtJCG

GCU

GAU

GAU

GAC

GCU

GCC

GUU

GCC

GAU

GAC

GUC

GAU

GCC

GAU

GCC

GtU

GCU

GAU

GAC

UCCAAGUG

UAUGUCAG

UAUACUAC

CAUGCUGG

GGCACGGG

UACCUCAC

UCCUGUAU

UGUGAGUG

GACAACCA

GGACAGUG

CGGAUAUC

GACACAGA

CAGAUUCU

UCUCCAGC

UGACACGG

UAAAAGGA

CAGAUUUU

TJUUGAAGU

UGCAGGGA

121 4210 CCUAGAAG AGAA GGCUCC ACCAGAGAAACACACGUUGtJGGUACAUUACCUGGUA GGAGCCA GCU CUTJCUAGG

I'

122 Table VI: Mouse flk- 1 VEGF Receptor -Hammerhead Ribozvme and Substrate Seauence nt.

Posi tion HH.Ribozyne Sequence Substrate 13 CCGtJACCC CUGAUGA X GAA AUUICGCCC GGGCGAAIJU GGGUACGG 18 31 37 10 44 46 50 55 59 61 66 67 83 97 114 115 169 171 178 180 197 204 212 213 215

GGGTJCCCG

UCGACCUC

AUACCGUC

CUUAUCGA

AGCUIJAUC

AUCAAGCU

UCGAUAUC

GAAUUCGA

CCGAAUUC

UGGGCCCG

CUGGGCCC

GGCUGCGG

AGCCAGGtJ

GUCCGCGG

UGUCCGCG

ACCGGGGA

AGACCGGG

CAGCGCAA

CGCAGCGC

AGAGGCGG

AAGUCACA

CCGCAAAG

CCCGCAAA

GGCCCGCA

CUGAUGA X GAA ACCCAALTU CUGAUGA X GAA AGGGGGGU CUGAUGA X GAA ACCUCGAG CUGAUGA X GAA ACCGUCGA CUGAUGA X GAA AUACCGUC CUGAUGA X GAA AUCGAUAC CUGAUGA X GAA AGCUUAUC CUGAUGA X GAA AUCAAGCU CUGAUGA X GAA AUAUCAAG CUGAUGA X GAA AUUCGAUA CUGAUGA X GAA AAUTUCGAU CUGAUGA X GAA ACACAGUC CUGAUGA X GAA AUCCCGGC CUGAUGA X GAA AUCGGGUC CUGAUGA X GAA AAUCGGGU CUGAUGA X GAA AGCGCGGG CUGAUGA X GAA AGAGCGCG CUGAUGA X GAA ACCGGGGA CUGAUGA X GAA AGACCGGG CUGAUGA X GAA AUGGCCCC CUGAUGA X GAA AGGCGGUA CUGAUGA X GAA AGtJCACAG CUGAUGA X GAA AAGUCACA CUGAUGA X GAA AGAAGUCA

AAUUGGGUA

ACCCCCCUC

CUCGAGGUC

UCGACGGUA

GACGGUAUC

GUAUCGAUA

GAUAAGCIJ

AGCUtJGAUA

CUUIGAUAUC

UAUCGAAUU

AUCGAAUUC

GACUGUGUC

GCCGGGAUA

GACCCGALTI

ACCCGAUUC

CCCGCGCUC

CGCGCUCUC

UCCCCGGUC

CCCGGUCUU

GGGGCCAUA

UACCGCCUC

CUGUGACUtJ

UGUGACUUC

UGACUUCUU

*CGGGACCC

GAGGUCGA

GACGGUAU

UCGAUAAG

GAIJAAGCU

AGCUUTGAU

GAUAtJCGA

UCGAALJUC

GAAUUCGG

CGGGCCCA

GGGCCCAG

CCGCAGCC

ACCUGGCU

CCGCGGAC

CGCGGACA

UCCCCGGU

CCCGGUCU

UTUGCGCUG

GCGCUGCG

CCGCCUCU

UGUGACU

CUUUGCGG

UUUGCGGG

UGCGGGCC

123 a.

a a a a a a a. a a a a 216 241 262 306 312 316 323 324 347 10 355 356 367 368 369 370 372 376 387 405 414 415 416 424 432 433 438 439 442 471

TJGGCCCGC

CAGGCACA

UGGGCACA

GCGACAGC

CACAGAGC

GAACCACA

CCACGCAG

UCCACGCA

AACCCACA

GCCAGUCA

CGCCAGUC

AUGGAGAA

GAUGGAGA

GGAUGGAG

GGGAUGGA

GGGGGAtJG CUtJGGGGG

UGUGUGCU

AUUGUCAG

IJUUGCCAA

ALTIUGCCA

TJAtUUG CC

AAGGGUUG

GUAAUCUG

AGUAAUCU

CUGCAAGU

CCUGCAAG

UCCCCUGC

UUEGGGCCA

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CEJGAUGA X CUGAULGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X4 CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X GAA AAGAAGUC GAA ACUCCUUC GAA AGCCCAGU GAA AGCAGCGC GAA ACAGCUAG GAA AGCGACAG GAA ACCACAGA GAA AACCACAG GAA AGGCGGCU GAA ACCCACAG GAA AACCCACA GAA AUCGCCAG GAA AAUCGCCA GAA AAAUCGCC GAA AAAAUCGC GAA AGAAAAUC GAA AUGGAGAA GAA AGCUEJGGG GAA AUGUCUUIJ GAA ALtUGUCAG GAA AAUUGUCA GAA AAAtJUG.UC GAA AUUUGCCA GAA AGGGUEJGU GAA AAGGGUUG GAA AUCUGAAG GAA AAUCUGAA GAA AGUAAUCU GAA AGCCAGTJC GACUUCUUU GCGGGCCA GAAGGAGUC

UGUGCCUG

ACUGGGCUC

UGUGCCCA

GCGCUGCUA

GCUGUCGC

CUAGCUGUC

GCUCUGUG

CUGUCGCUC

UGUGGUUC

UCUGUGGLTU CUGCGtJGG CUGUGGUUC

UGCGUGGA

AGCCGCCUC

UGUGGGUU

CUGUGGGUU1

UGACUGGC

UGUGGGUUTJ GACUGGCG CUGGCGAUU UUCUCCAU UGGCGAUUU UCUCCAUC GGCGAUUUJ CUCCAUCC GCGAUUUUC

UCCAUCCC

GAUUIJUJCUC CAUCCCCC UUCUCCAUC CCCCCAAG CCCAAGCUC

AGCACACA

AAAGACAUA CUGACAAU CUGACAAUtJ UUGGCAAA UGACAALTUU UGGCAAAU GACAAUUUU GGCAAAUA UGGCAAAUA CAACCCUU ACAACCCTU CAGAUEJAC.

CAACCCUUC AGAUTACU CUUCAGAUU ACUEJGCAG UELJCAGAUULA CUUG CAGG AGAUUACUU GCAGGGGA GACUGGCUU UGGCCCAA ACUGGCUUIJ GGCCCAAU 472 AUTUGGGCC CUGAUGA X GAA AAGCCAGU 124 484 AUCACGCU CUGAUGA X GAA AGCAUUGG 493 494 507 509 538 540 542 543 10 555 561 562 573 583 593 602 605 615 621 626 633 634 635 639 641 645 646 652 653

UTUCCUCAG

UUUtCCUCA

GUCACCAA

CAGUCACC

GCAGAAGA

UUGCAGAA

UUUIJGCAG

GUTJUGCA

GGAAUGGU

ACCCTJGGG

CACCCUGG

UCAUUUCC

GGCUCCAG

AGCACUUG

CCCGGUAC

CGUCCCGG

GCUAUGUC

GtJGGAGGC

AAACAGUG

UAGACAUA

AUAGACAU

CAUAGACA

CGAACAUA

CUCGAACA

UAAUCtICGC

GUAAUCUCC

UGAUCUGUC

GUGAUCUGC

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X =UAUGA XC =UAUGA XC =UAUGA XC 'UGAUGA XC "TGAUGA X ~'UGAUGA XC UTGAUGA XC GAA AUCACGCU GAA AAUCACGC GAA ACCCUUUC GAA AUACCCU GAA ACUGUCAC GAA. AUACUGUC GAA AGAUACUG GAA AAGAUACU GAA AGUGUUIJUJ GAA AUGGUGAG GAA AAUGGUGA GAA ACCACCCU GAA AUCAUTUUC GAA AGGCUCCA GAA AGCACUUG GAA ACGAGCAC GAA ACGUCCCG 3AA AUGUCGAC .3AA AGGCUAUG 33AA ACAGUGGA 3AA AACAGUGG 'AA AAACAGUG ;AA ACAUAAAC 'AA AGACAUAA ,AA ACAUAGAC 'AA AACAUAGA YAA AUCUCGAA AA AAUCUCGA CCAAUGCIJC

AGCGUGAU

AGCGUGAULJ

CUGAGGAA

GCGUGAUUC

UGAGGAAA

GAAAGGGUA

ULJGGUGAC

AAGGGUAUU

GOUGACUG

GUGACAGUA

UCUUCUGC

GACAGUAUC

UUCUGCAA

CAGUAUCUU

CUGCAAAA

AGUAUCULJC

UGCAAAAC

AAAACACUC

ACCAUUCC

CUCACCAUU

CCCAGGGU

UCACCALUC

CCAGGGUG

AGGGUGGUU

GGAAAUGA

GAAAUGAUA

CUGGAGCC

UGGAGCCUA

CAAGUGCU

CAAGUGCUC

GUACCGGG

GUGCUCGUA

CCGGGACG

CGGGACGUC

GACAUAGC

GUCGACAUA

GCCUCCAC

CAUAGCCUC

CACUGUUU

UCCACUGUU

UAUGUCUA

CCACUGUUU

AUGUCUAU

CACUGUJEJA

UGUCUAUG

GUUJUAUGUC

UAUGUTUCG

UUAUGUCUA

UGUUCGAG

GUCUAUGUU CGAGAUUIA UCUAUGUUC

GAGAUUAC

UUCGAGAUU

ACAGAUCA

UCGAGAUUA

CAGAUCAC

UUACAGAUC ACCAUTUCA 659 UGAAUGGU CUGAUGA X GAA AUCUGUAA 125 0e 0' 665 666 669 674 678 696 701 705 735 10 749 753 754 755 762 770 772 774 775.

781 785 787 800 801 804 805 822 823 824 840 845

AGGCGAUG

GAGGCGAU

ACAGAGGC

CACUGACA

UGGUCACU

AUGUACAC

CGGUGAUG

UTJCUCGGU

CGGCAGGG

UUGAAAUC

AGGULTUGA

GAGGUUUG

UGAGGUUUI

GACACATU

CGCAAAGA

AGCGCAAA

CUAGCGCA

CCUAGCGC

UGGAUACC

UUCUGGA

CUEUUCUG

CCGGAACA

UCCGGAAC

CCAUCCGG4

UCCAUCCG

IJCCCAGGA

GUCCCAGG

UGUCCCAG

GUAAAGCC

GGAGAGUA

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUJGA X CUGAUGA X4 CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X UGAUGA X UGAUGA X 'UGAUGA X GAA AUGGUGAU GAA AAUGGUGA GAA AUGAAUGG GAA AGGCGAUG GAA ACAGAGGC GAA AUG CCAUG GAA ACACGAUG GAA AUGUACAC GAA AUCACCAC GAA ACCCUCGG GAA AUCGACCC GAA AAUCGACC GAA AAAUCGAC GAA AGGUUJUGA GAA ACACAUTUG GAA AGACACAU GAA AGAGACAC GAA AAGAGACA GAA AGCGCAAA GAA ACCUAGCG GAA AUACCUAG GAA AUCUCULU GAA AAUCUCU GAA ACAAAUCU GAA AACAAAUC GAA AUUCUGLU .,AA AAUUCUGU ,AA AAAUUCUG 3AA AUCUCGCU 3AA AGCCUAUC AUCACCAUU

CAUCGCCU

UCACCAUTUC

AUCGCCUC

CCAUUCAUC

GCCUCUGU

CAUCOCCUC

UGUCAGUG

GCCUCUGUC

AGUGACCA

CAUGGCAUC

GUGUACAU

CAUCGUGUA

CAUCACCG

GUGUACAUC

ACCGAGAA

GUGGUGAUC

CCCUGCCG

CCGAGGGUC

GAUULUCAA

GGGUCGAUU

UCAAACCU

GGUCGAUUU

CAAACCUC

GUCGAUUUC

AAACCUCA

UCAAACCUC

AAUGUGUC

CAAUGUGUC

UCUUUGCG

AUGUGUCUC

UUUGCGCU

GUGUCUCUU UGCGCUAG UGUCUCtJUU

GCGCUAGG

UUUJGCGCUA

GGUAUCCA

CGCUAGGUA UCCAGAAA CUAGGUAUC CAGAAAAG AAAGAGAtJU

UGUTUCCGG

AAGAGAUUrj

GUUCCGGA

AGAUTUUGUU

CCGGAUGG

GAUTJUGUUC CGGAUGGA AACAGAAUU

UCCUGGGA

ACAGAAULU

CCUGGGAC

CAGAAUTUUC

CUGGGACA

AGCGAGAUA

GGCUUUAC

GAUAGGCUU UACUCUCC 0 126 846 GGGAGAGU CUGAUGA X GAA AAGCCTJAU see of a.

0004 eve* 847 850 852 859 860 867 872 885 887 888 903 917 919 923 925 927 932.

936 939 945 948 953 955 960 961 962 972 973

GGGGAGAG

ACUGGGGA

UAACUGGG

GAUCAUGU

IJGAUCAUG

GCAUAGCU

UGCCGGCA

UCACAGAA

CCUCACAG

GCCUCACA

UCAUCAUU

UAGACUGA

GAUAGACU

ACAUGAUA

GUACAUGA

AUGUACAU

CAACUAUG

ACCACAAC

ACAACCAC

UAUCCUAC

CUAUAUCC

AAAUCCUA

AUAAAUCC

ACAIJCAUA

CACAUCAU

UCACAUCA

GGGCUCAG

GGGGCUCA

CUGAUGA X GAA AAAGCCUA CUGAUGA X GAA AGTJAAAGC CUGAUGA X GAA AGAGUAAA CIJGAUGA X GAA ACUGGGGA CUGAUGA X GAA AACUGGGG CUGAUGA X GAA AUCAUGUA CUGAUGA X GAA AGCUGAUC CUGAUGA X GAA ACCAUGCC CUGAUGA X GAA AGACCAUG CUGAUGA X GAA AAGACCAU CUGAUGA X GAA AUCUELJUGC CUGAUGA X GAA AGGUUtJCA CUGAUGA X GAA AUAGGUUUT CUGAUGA X GAA ACUGAIJAG CUGAUGA X GAA AGACUGAU CUGAUGA X GAA AUAGACUG CUGAUGA X GAA ACAUGAUA CUGAUGA X GAA ALJGUACAU CUGAUGA X GAA ACUAUGUA CUGAUGA X GAA ACCACAAC CUGAUGA X GAA ACAACCAC CUGAUGA X GAA AUCCUACA :UGAUGA X GAA AUAUCCUA UGAUGA X GAA AUCCUAUA UGAUGA X GAA AAUCCIJAU UJGAUGA X GAA AAAUCCIJA .GAUGA X GAA AUCACAUC .GAUGA X GAA AAUCACAU AUAGGCUUU ACUCUCCC UAGGCUUUA CUCIJCCCC GCUTUt~ACUC

UCCCCAGU

UULJACUCUC CCCAGIJUA UCCCCAGTJU ACAUGAUC CCCCAGUUtA CAUGAUCA UACAtJGAUC

AGCUAUGC

GAUCAGCUA UGCCGGCA GGCAUGGUC

UUCUGUGA

CAUGGUCUU

CUGUGAGG

AUGGUCUUC UGUGAGGC GCAAAGAUC AAUGAUGA UGAAACCUA UCAGUCUA AAACCUAUC AGUCUAUC CUAUCAGUC UAUCAUGU AUCAGUCUA

UCAUGUAC

CAGIJCUAUC AUGtJACAU UAUCAUGUA CAUAGTJUG AUGUACAUA GUUGUGGU UACAUAGUJT GUGGUUGU GUTUGUGGUTU

GUAGGAUA

GUGGUUGUA

GGAUAUAG

UGUAGGAUA UAGGAUU UAGGAUAUA GGAUUtJAU UAUAGGAUU UAUGAUGU AUAGGAUUJI AUGAUGUG UAGGAUtJUA

UGAUGUGA

GAUGUGAUTI

CUGAGCCC

AUGUGAUrJC UGAGCCCC CAUGAAAUU GAGCUATJC 993 GAUAGCUC CUGAUGA X GAA AUtTLCAUG 127 999 CCGGCAGA CUGAUGA X GAA AGCUCAAU AUIJGAGCUA UCUGCCGG 1001 1017 10.20 1022 1023 1027 1030 1047 10 1059 1063 1064 1065 1076 15 1078 1084 1085 1091 1093 1096 1099 1107 1110 1130 1131 1132 1154 1155 1156 1157

CTJCCGGCA

UUU2AAGAC

CAAUUUJAA

UACAAUUU

GUACAAUUT

CGCUGUAC

UCUCGCUG

CCCACAUU

GUGAAAUC

CCAGGUGA

GCCAGGUG

UGCCAGGU

AAGGUGGA

UGAAGGUG

AGACUUtJG

GAGACUUU

UAUGAUGA

CUIJAUGAU

CUUCUUAU

AAUCUtJCU

CGGUUUAC

UCCCGGUU

UCCCAGGA

GUCCCAGG

AGUCCCAG

TJGCUCAAA

GUGCUCAA

GGUGCUCA

AGGUGCUC

CUGAtJGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X4 CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X UGAUGA X UGAUGA X UGAUGA X GAA AUAGCUCA GAA AGUtJUUUC GAA ACAAGUUU GAA AGACAAGU GAA AAGACAAG G.AA- AUUUAAGA GAA ACAAUUTUA GAA AGCUCUGU GAA AGCCCCAC GAA AUCAAGCC GAA AAUCAAGC GAA AAAUCAAG GAA AGUGCCAG GAA AGAGUGCC GAA AGGUGGAG GAZA AAGGUGGA GAA ACUUU2GAA GAA AGACUUUJTG GAA AUGAGACU GAA AUGAUGAG GAA AUCUUCLU GAA ACAAUCUU GAA AGGGUUJC 3AA AAGGGULU 3AA AAAGGGLU 7AA ACAUCUUC ,AA AACAUCUUJ ZAA AAACAUCU 3AA AAAACAUC

UGAGCUAUC

GAAAAAMt

AAACUTUGUC

ACUGUCU

CUUGUCLTIJP

UCUUIAAAUU

UAAAUUGUA

ACAGAGCUC

GUGGGGCUU

GGCUTUGALU

GCUUGAUUUT

CUUGAUUUC

CUGGCACUC

GGCACUCUC

CUCCACCUU

UCCACCUTJC

UUCAAAGUC

CAAAGUCUC

AGUCUCAUC

CUCAUCAUA

AAGAAGALUU

AAGAUUGUA

GAAACCCUJ

AAACCCUUJ

AACCCUUUC

GAAGAUGUtJ

AAGAUGUUU

AGAUGUULTU

GAUGUUUU

-UGCCGGAG

JGUCUUAAA

'UUAAAUUG

yAAAUUGUA

LAAUUGUAC

GUACAGCG

CAGCGAGA

AAUGUGGG

GAUUUCAC

UCACCUGG

CACCUGGC

ACCUGGCA

UCCACCLTEJ

CACCUUCA

CAAAGUCU

AAAGUCUC

UCAUCAUA

AUCAUAAG

AUAAGAAG

AGAAGAUU

GUAAACCG

AACCGGGA

UCCUGGGA

CCUGGGAC

CUGGGACU

UTJUGAGCA

UTJGAGCAC

UGAGCACC

GAGCACCU

128 1166 1173 1205 1215 1220 1236 1246 1253 1254 1257 1263 1264 1276 1277 1278 1279 1281 1285 1286 1287 1291 1304( 13061 1307C 1330 t 1335 1341 1 1352 1354 G

CUALAUUGUC

ACACUUIJC

CACAGGUG'

CUGGACGC

GUCCACUG

UtUUCUU

AAAUGUUC

CUCGGACA

ACUCGGAC

UGAACUCG

UUUGUGUG

CUUIJGIGU

AGCAAUAA

AAGCAAUA

AAAGCAAU

GAAAGCAA

CCGAAAGC

NCUACCGA

CACUACCG

CCACUACC

AUCCCACC

7CACCAAAC

JJCCACCAC

'UUCCACCC

JCGGAC1JU C

;GGAUTUCGC

rUJCACAGG C

ACUGAGAC

UAACUGA c CUGAUGA X GAA AGGUGCUC CUGAUGA X GAA AUUGUCAA CUGAUGA X GAA AUUCCCCU CUGAUGA X GAA ACACAGGU CUGAUGA X GAA ACGCUACA CUGAUGA X GAA AUCAUCCG CUGAUGA X GAA AUUUCtJCU CUGAUGA X GAA AUGUEJCUA CUGAUGA X GAA AAUGUUCU CUGAUGA X GAA ACAAAUGU CUGAUGA X GAA ACUCGGAC CUGAUGA X GAA AACUCGGA CUGAUGA X GAA AGGCUULUG CUGAUGA X GAA AAGGCUUU CUGAUGA X GAA AAAGGCUU CUGAUGA X GAA AAAAGGCU CUGAUGA X GAA AUAAAAGG :UGAUGA X GAA AGCAAUAA :UGAUGA X GAA AAGCAAUA UTGAUGA X GAA AAAGCAAU 'TUGAUGA X GAA ACCGAAAG 'UGAUGA X GAA AUUUCAUC 'UGAUGA X GAA AGAUUIJCA .UGAUGA X GAA AAGAUUTJC :UGAUGA X GAA ACUGCCCA 'GAUGA X GAA ACUGACU UGAUGA X GAA AUUCGGAC LIGAUGA X GAA ACUTJCACA UGAUGA X GAA AUACUUCA

GAGCACCU

UUGACAAU,

AGGGGAAU

ACCUGUGU

UGUAGCGU(

CGGAUGAU(

AGAGAAAUJ

UAGAACAUE

AGAACAULTI

ACAUUUGUC

GUCCGAGTJI

UCCGAGUUC

CAAAGCCUU

AAAGCCUUU

AAGCCUUUU

AGCCUUUUA

CCIUUAU

TJUAUUGCUJ

UAUUGCLUU

AUUGCLUUC

CLJUUCGGUA

GAUGAAAUC

UGAAAUCU

GAAAUCULTU

UGGGCAGUC

AGUCAAGUC

GUCCGAAUC

UGUGAAGUA

UGAAGUAUC

U GACAAUAG A~ GAAAGUGU.

k. CACCUGTJG k. GCGUCCAG

CAGUGGAC

2 AAGAGAAA k GAACAUUU J UGUCCGAG

JGUCCGAGU

CGAGUUCA

TCACACAAA

ACACAAAG

UUAUUGCU

UAIJUGCUU

AUUtGCUUU

UTUGCJUJC

GCLUUCGG

UCGGUAGU

CGGUAGUG

GGUAGUGG

GUGGGAUG

LUUJGGUGG

UGGUGGAA

GGUGGAAG

AAGUCCGA

CGAAUCCC

CCUGUGAA

UCUCAGUJ

UCAGUTUAC

3 0 13 56 GGGUAACU CUGAUGA X GAA AGAUACULJ AAGUAUCIJC AGLTUACCC 129 1360 1361 1369 1375 1377 1385 1404 1409 1415 10 1425 1428 1440 1446 1478 1485 1488 1491 15031 1504 15051 1530 1532 1534C 1539 1 1548t 1560 1 1574 C 1578 1580 C

AGCUGGGU

GAGCUGGG

GAIJAUCAG

CCAUUUGA

UACCALUU

CAUUTJCUG

UJUGGACUC

UGUAGUTUG

UCAUUGUG

UCGCCAAC

UCAUCGCC

AUGAUGGU

ACUTJCCAU

UGACCGUG

GUGAGGAU

UUGGUGAG

GGGUUGGU

LYCCALTUJGA

CUCCAUUG

JCTJCCAU

kCCAGAGA

:AACCAGAC

:ACAACCAC

~CAUTUCAC C

JGGGGUGGC

flJCUCACCC

;CGAGAUCC

LUAGGCGAC

CAUAGGCC

CUGAUGA X GAA ACUGAGAU CUGAUGA X GAA AACUGAGA CUGAUGA X GAA AGCUGGGU CUGAUGA X GAA AUCAGGAG CUGAUGA X GAA AUAUCAGG CUGAUGA X GAA ACCAUtTUG CUGAUGA X GAA AUGGGCCU CUGAUGA X GAA ACUCAAUG CUGAUGA X GAA AGIJUGGAC CUGAUGA X GAA AUCAUUGU CUGAUGA X GAA ACAAUCAU CUGAUGA X GAA AGIJUCAUC CUGAUGA X GAA AUGGUGAG CUGAUGA X GAA AGUIJUCCU CUGAUGA X GAA ACCGUGUA CUGAUGA X GAA AIJGACCGU CUGAUGA X GAA AGGAUGAC CUGAUGA X GAA AUGGGGLU CUGAUGA X GAA AAUGGGGU 7UGAUGA X GAA AAAUGGGG UGAUGA X GAA ACCAUGUG UGAUGA X GAA AGACCAUG :UGAUGA X GAA AGAGACCA UGAUGA X GAA ACCAGAGA UTGAUGA X GAA ACATUCAC UTGAUGA X GAA AUCtJGGGG 'TUGAUGA X GAA AGGCUUUC .'TGAUGA X GAA AUCAAGGC ,'UGAUGA X GAA AGAUCAAG AUCUCAGIJU

ACCCAGCU

UCUCAGUIJA

CCCAGCTJC

ACCCAGCUC

CUGAUAUC

CUCCUGAUA

TJCAAAUGG

CCUGAUAUC

AAAUGGUA

CAAAUGGUA

CAGAAAUG

AGGCCCAUU

GAGUCCAA

CAUTJGAGUC

CAACUACA

GUCCAACUA

CACAAUGA

ACAAUGAUU

GUUGGCGA

AUGALTUGUU

GGCGAUGA

GAUGAACUC

ACCAUCAU

CUCACCAUC

AUGGAAGU

AGGAAACUA

CACGGUCA

UACACGGUC

AUCCUCAC

ACGGUCAUC

CUCACCAA

GUCAUCCUC

ACCAACCC

AACCCCAUU

UCAAUGGA

ACCCCAUUTJ CAAUGGAG CCCCAUUUC

AAUGGAGA

CACAUGGUC

UCUCUGGU

'CAUGGUCUC tJCUGGUUG UGGUCUCUC

UGGUTJGUG

UCUCUGGUU

GUGAAUGU

GUGAAUGUC

CCACCCCA

CCCCAGAUC

GGUGAGAA

GAAAGCCUEJ

GAUCUCGC

GCCUUGAUC

UCGCCUAU

CUUGAUCUC

GCCUAUGG

UCUCGCCUA UGGATJUCC 1585 GGAAUCCA CUGAUGA X GAA AGGCGAGA 130 1591 CUGGUAGG CUGAUGA X GAA AUCCAUAG 1592 1595 1601 1619 1632 1634 1645 1659 10 1667 1677 1691 1694 1718 1723 1726 1750 1751 1752 1770 17761 17901 1800 18212 1825C 1833 C 1836 C 1853 P 1859 1862C

ACUGGUAG

CAUACUGG

UGGUCCCA

TJGCAUGUC

UEJGGCGUA

GGUUtGGCG

GUGCAGGG

UACCACUG

GCUGCCAG

GCUUECUUtC

GUCUGIJAG

CGGGUCUG

UACAAGCA

TJUCUUULAC

CCAUUECUj

CCCCUGGA

CCCCCUGG

CCCCCCUG

GUGACUUC

jrJUUUGGU

JCAGGGCA

JJuCCUUCcC kGCGUACUC 'ACCAGCG C

;CUUGGAUC

CAGCUUJGC

LCAACGCUC

LUUUGUAC C 'ACAUUtUGC CUGAUGA X GAA AAUCCAUA CUGAUGA X GAA AGGAAUCC CUGAUGA X GAA ACUGGUAG CUGAUGA X GAA AUGUCtJGC CUGAUGA X GAA ACUGUGCA CUGAUGA X GAA AGACUGUG CUGAUGA X GAA AGGGUTJGG CUGAUGA X GAA AUGUGGUG CUGAUGA X GAA ACCACUGG CUGAUGA X GAA AGCUGCCA CUGAUGA X GAA AG CAGG CU CUGAUGA X GAA AGGAGCAG CtJGAUGA X GAA ACGGGCUUC CUGAUGA X GAA AGCAUACG CUGAUGA X GAA ACAAGCAU CUGAUGA X GAA AUCCUCCA CUGAUGA X GAA AAUCCUCC -UGAUGA X GAA AAAIJCCUC MUGAUGA X GAA AUCUUGtU UJGAUGA X GAA ACTUCGAU UTGAUGA X GAA AUtJGGIJUU UGAUGA X GAA AUCAGGGC UTGAUGA X GAA ACAGULJ :UGAUGA X GAA ACUUACAG VUGAUGA X GAA ACCAGCGU ~UGAUGA X GAA AUGACCAG ,'UGAUGA X GAA ACACGUJLG UGAUGA X GAA ACGCUGAC UGAtJGA X GAA ACAACGCU CUAUGGAUU

CCUACCAG

UAUGGAUUC

CUACC-AGU

GGAUtJCCUA

CCAGIJAUG

CUACCAGUA

UGGGACCA

GCAGACAUU

GACAUGCA

UGCACAGUC

UACGCCAA

CACAGUCUA

CGCCAACC

CCAACCCYC

CCCUGCAC

CACCACAUC

CAGUGGUA

CCAGUGGUA

CUGGCAGC

UGGCAGCIJA

GAAGAAGC

AGCCTJGCtJC

CUACAGAC

CUGCTJCCtJA

CAGACCCG

AAGCCCGUA UGCLtTJGUA CGUAUGCUU

GUAAAGAA

AUGCUUGUA AAGAAUGG UGGAGGAUU

UCCAGGGG

GGAGGAUUU

CCAGGGGG

GAGGAULJUC

CAGGGGGG

AACAAGAUC

GAAGUCAC

AUCGAAGUC

ACCAAAAA

AAACCAAUA

UGCCCUGA

GCCCUGAUU

GAAGGAAA

AAAACUGUA

AGTJACGCU

CUGUAAGUA

CGCUGGUC

ACGCtJGGUC

AUCCAAGC

CUGGUCAUC

CAAGCUGC

CAACGUGUC

AGCGUUGU

GUCAGCGUU

GUACAAAU

AGCGTJUGUA CAAAUGUG 131 1878 GCUUUGUTJ CUGAUGA X GAA AUGGCLIUC 1905 AAGGAGAU CUGAUGA X 1908 1910 1913 1914 1923 1930 1938 10 1939 1982 1988 2008 2012 2013 2022 2030 2037 2042 2054 2058 2072 2076 2085 2086C 2096C 2104t 2106 1 2107C 2129 L

UGGAAGGA

CAUGGAAG

UCACAUGG

AUCACAUG

GGACCCCU

AAUUUCAG

UGCACAGU

UUGCACAG

ACAACAGG

CAGUGCAC

CUCAAACG

GGUUCUCA

AGGLUJCUC

UACCACGU

CAAGCtIUG

UGUGAGCC

UUGCCUGU

LGUGGACC

CCCAUGUG

GUGUGAGU

kCUGGUGU

-TUCUUGCA

7UUCUUGC

;AGCAUCCC

JUIJCCAAAC

~GUUUCCAC

:AGUUUCCC

YGUUAGAA C CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CtJGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X UGAUGA X 'UGAUGA X UGAUGA X 'IJGAUGA x 'UGAUGA X UTGAUGA x( UTGAUGA x UGAUGA X GAA ACCCUCUC GAA AUGACCCU GAA AGAUGACC GAA AGGAGAUG GAA AAGGAGAU GAA AUCACAUG GAA ACCCCUGA GAA AUUUCAGG GAA AAUUUCAG GAA ACACACUC GAA ACAGGGAC GAA AtJUUCUGU GAA ACGUAUUU GAA AACGUALJU GAA AGGUUCUC GAA ACCACGUG GAA AGCUUGUA GAA AGCCAAGC GAA AUGUUJGCC GAA ACCGAUGU GAA AULJCGCCC GAA AGUGAUIJC GAA ACUGGUGU GAA AACUGGUG 3AA AGUtJCUUG 3AA AGCAUCCA 3AA AGAGCAUC ,AA AAGAGCAU 7AA ACAUGGUG GAAGCCAUC

AACAAAGC

GAGAGGGUC

AUCUCCUU

AGGGUCAUC UCCtJUCCA GGUCAUCUC CtUUCCAUG CAUCUCCUU

CCAUGUGA

AUCUCCUtJC CAUGUGAU CAUGUGAUC

AGGGGUCC

UCAGGGGUC

CUGAAAU

CCUGAAAUU

ACUGUGCA

CUGAAAUUA

CUGUGCAA

GAGUGUGUC

CCUGUEJGU

GUCCCUGUU

GUGCACUG

ACAGAAAUA

CGUUUGAG

AAAUACGUUI

UGAGAACC

AAUACGUUU

GAGAACCU

GAGAACCUC

ACGUGGUA

CACGUGGUA

CAAGCUUG

UACAAGCUU

GGCUCACA

GCUTJGGCUC

ACAGGCAA

GGCAACAUC

GGUCCACA

ACAUCGGUC CACAUGGG GGGCGAAUC

ACUCACAC

GAAUCACUC

ACACCAGU

ACACCAGUU

UGCAAGAA

CACCAGUUU

GCAAGAAC

CAAGAACtJU

GGAUGCUC

UGGAUGCUC

UTUUGGAAA

GAUGCUCUU

UGGAAACU

AUGCUCUULJ

GGAAACUG

CACCAUGUU UUCTJAACA 132 2130 2131 2132 2134 2151 2153 2157 2165 2166 10 2167 2177 2179 2198 2202 2203 2207 2212 2218 2239 2247 2256 22591 2262 2265 2286 2296 2305 2319 C 2331 C 2341 I

CUGUIJAGA

GCTJGUUAG

UGCtJGUUA

UGUGCUGU

ACAAUCAA

CCACAAUC

AAUGCCAC

CAUtJCTGA

GCAUUCTJG

GGCAUUCU

CCUGCAGA

GUCCUGCA

AGCAAACA

GCAGAGCA

AGCAGAGC

CUTUGAGCA

CUUAUCIU

GGUCUUTCU

GACCAGGC

AGCUGLUU

kGGAUGAU

LJCUAGGAU

2GCIJCUAGC kUGCGCtJCC

JUUCCGGUC

WUUCUCCAC

JGUUGUCUC

UCUCGCCC

;UCACUtUcC rGCLJGGGcC CUGAUGA X GAA AACATJGGU CUGAUGA X GAA AAACAUGG CUGAUGA X GAA AAAACAUG CUGAUGA X GAA AGAAAACA CUGAUGA X GAA AUGUCAUU CUGAUGA X GAA AGAUGUCA CUGAUGA X GAA--AUCAAGAU CUGAUGA X GAA AUGCCACA CUGAUGA X GAA AAUGCCAC CUGAUGA X GAA AAAUGCCA CUGAUGA X GAA AGGCAUtJC CUGAUGA X GAA AGAGGCAU CUGAIJGA X GAA AGUCGCCU CUGAUGA X GAA ACAUAGUC CUGAUGA X GAA AACAUAGU YJGAUGA X GAA AGCAAACA CUGAUGA X GAA AGCAGAGC :UGAUGA X GAA AUCUULGAG UGAUGA X GAA AUGUCLUU UGAUGA X GAA ACCAGGCA -7UGAUGA X GAA AGCUGUU UGAUGA X GAA AUGAGCUG .UGAUGA X GAA AUGAUGAG UTGAUGA X GAA AGGAUGAU 'UGAUGA X GAA AUCAUGGG .'UGAUGA X GAA AUUUCCGG ,'UGAUGA X GAA AUUtCUCCA IJGAUGA X GAA AtJGGLJUGU UGAUGA X GAA AUGGUCUC UGAUGA X GAA AGUCACUTJ ACCAUGUTJU

UCUAACAG

CCAIJGUUUU

CUAACAGC

CAUGUtUUC

UAACAGCA

UGUUUtJCUA

ACAGCACA

AAUGACAUC

UEJGAUUGU

UGACAUCUU

GAUUGUGG

AUCUUGAUIJ

GUGGCAUU

UGUGGCAUU

UCAGAAUG

GUGGCAUEJU

CAGAAUGC

UGGCAUUUC

AGAAUGCC

GAAUGCCUC

UCUGCAGG

AUGCCUCUC

UGCAGGAC

AGGCGACUA

UGIJUUGCU

GACUAUGUU

UGCUCUGC

ACUAUGUUU

GCUCUGCU

UGUUUGCUC

UGCUCAAG

GCUCUGCUC

AAGAUAAG

CUCAAGAUA

AGAAGACC

AAAGACAUrJ

GCCUGGUC

UGCCtJGGUC

AAACAGCU

AAACAGCUC

AUCAUCCU

CAGCUCAUC AUCCtJAGA CUCAUCAIIC

CUAGAGCG

AUCAUCCUA

GAGCGCAU

CCCAUGAUC

ACCGGAAA

CCGGAAAUC

UGGAGAAU

UGGAGAAUC

AGACAACA

ACAACCAUU

GGCGAGAC

GAGACCAUU

GAAGUGAC

AAGUGACUtJ GCCCAGCA 133 2351 2359 2362 2373 GAUUJLCCA

CUGAUG

UGGGGUAG

CUGAUG

GUGUGGGG

CUGAUG.

AACCAUGU'CUGAUG

A

A

A

2374 2381 2382 2403 2410 10 2411 2418 2421 2449 2451 2481 2483 2505 2508 2532 2534 25351 2538 2541 2567 2574 1 2577 1 2578C 2580 C 2583 G

GAACCAU,

UGUCUUU

UUGUCTEJI

GAAUCUU(

AAUGCCUC

CAAUGCCI

CUCAGUAC

UCUCUCAC

CCUGCGGP

ACCCUGCC

CAG.GUGUJA

GGCAGGTJG

CAGCCAAG

GCACAGCC

AIJUAUGAA

CUAUUAUG

LJCUAUTUAU

CULUCUAU

.CACCUTUC

JGACLUCC

~GGAUAAU

~CGAGGAU

;ACGAGGA

CGACGAG

;UGCCGAC

3 CUGAUGA -3 CUGAUGA J3 CUGAUGA

:CUGAUGA

CUMGAUGA

J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA)

CUGAtJGA CIJGAUGA Y~ x x x x x x x x x x x

K

X GAA AUGCtJGGG X GAA AUUJUCCAG K GAA AGGALJUUC K GAA AUGUGUGG K GAA AAUGUGTJG CGAA ACCAUGUA GAA AACCAIJGU GAA ACCAGGGU GAA AUCUIJCUA GAA AAUCUUCU GAA AUG CCIJGA GAA ACAAUGCC GAA AGUCAGGU GAA AUAGUCAG GAA AGGCCUCC' GAA AGAGGCCU GAA ACAUUGCA GAA AGGACAU GAA AGCGUCUC GAA AGAGCGUC GAA AAGAGCGU GAA AUGAAGAG GAA AUUAUGAA GAA AGUUGGUC G.AA ACUJICCAA GAA AUGACIJUC GAA AAUGACUUJ GAA AUAAUGAC GAA AGGAUAAU CCCAGCAUC

UGGAAAUC

CUGGAAAUC

CUACCCCA

GAAAUCCIJA

CCCCACAC

CCACACAUrJ

ACAUGGUU

CACACAUIJA

CAUGGUUC

UACAUGGUU

CAAAGACA

ACAUGGUUC

AAAGACAA

ACCCUGGUA

GAAGAUUC

UAGAAGAUU

CAGGCAUU

AGAAGAUJTC

AGGCAUUG

UCAGGCAUU

GUACUGAG

GGCAUUGUA

CUGAGAGA

ACCUGACUA

UCCGCAGG

CUGACUAUC

CGCAGGGU

GGAGGCCUC

UACACCUG

AGGCCUCUA

CACCUGCC

UGCAAUGUC

CUUGGCUG

AAUGUCCUU

GGCUGUGC

GAGACGCUC

UUCATJAAU

GACGCUCUU

CAUAAUAG

ACGCUCUEJC

AUAAUAGA

CUCUUTCAUA AUAGAAG4G UtJCAUAAUA

GAAGGUGC

GACCAACUU

GGAAGUCA

UTUGGAAGUC

AUJUAUCCU

GAAGUCAUU

AUCCUCGU

AAGUCAUUA

UCCUCGUC

GUCAUUAUC

CUCGUCGG

AUUAUCCUC

GUCGGCAC

AUCCUCGUC

GGCACUGC

2586 GCAGUGCC CUGAUGA X GAA ACGAGGAU 134 2601 AACAUGGC CUGAUGA X GAA AUCACtJGC GCAGUGAUU GCCAUGUU 2609 2610 2612 2613 2619 2622 2623 2625 10 2628 2631 2634 2637 2646 2647 2681 2684 2687 2689 20 26911 2694 2701 2711C 2717 C 2738C 2743 C 2744E 2765 C 2766 U 2787 G

GCCAGAAG

AG CCAGAA

GGAGCCAG'

AGGAGCCA

ACAAGAAG

AUGACAAG

AAUGACAA

ACAAUGAC

AGGACAAU

CGUAGGAC

GUCCGTJAG

ACGGUCCG

GCCCGCUU

GGCCCGCU

UAGACAAG

CAAUAGAC

(JGACAAUA

CAUGACAA

JCCAUGAC

3GAUCCAU .JtICAU'CC :CAAGGGcC

;CICAUC

!AUAAGGCC

;GCAUCAtJ

C

rGGCAUCA

C

'CCUGGGG

C

rCCCTJGGGC GUUUUCC C CUGAUGA X GAA ACAUGGCA CUGAUGA X GAA AACAUGGC CUGAUGA X GAA AGAACAUG CUGAUGA X GAA AAGAACAU CUGAUGA X GAA AGCCAGAA CUGAUGA X GAA AGGAGCCA CUGAUGA X GAA AAGGAGCC CUGAUGA X GAA AGAAGGAG CUGAUGA X GAA ACAAGAAG CUGAUGA X GAA AUGACAAG CUGAUGA X GAA ACAAUGAC CUGAUJGA X GAA AGGACAAU CUGAUGA X GAA ACGGUCCG CUGAUGA X GAA AACGGUCC' CUGAUGA X GAA AGCCUGUC CUGAUGA X GAA AGUAGCCU CUGAUGA X GAA ACAAGUAG 7UGAUGA X GAA AGACAAGU -UGAUGA X GAA AUAGACAA 'UGAUGA X GAA ACAAUAGA UGAUGA X GAA AUCCAUGA .'UGAUGA X GAA AUUCAUCU UTGAUGA X GAA AGGGCAAU 'TUGAUGA X GAA AGCGtJUCA tJGAUGA X GAA AGGCAAGC tIGAUGA X GAA AAGGCAAG 'UGAUGA X GAA AUUtCCCAC UGAUGA X GAA AAUUCCCA UGAUGA X GAA AGLJUUCAG

UGCCAUGU

GCCAUGUtJ

CAUGUUCU

AUGUTUCUUJ

UUCUGGCUI

UGGCUCCLTI

GGCUCCUU(

CucctJUCUt

CUUCUUGUC

CUtJGUCAJTI GUCAUtIGUC

AUUGUCCUP

CGGACCGUL

GGACCGLUUA

GACAGGCUA

AGGCUACUU

CUACUUGUC

ACUUGUCUA

UTUGUCUALU

UCtJAUIJGUC

UCAUGGAUC

AGAUGAAUU

ALUGCCCUtJ

UGAACGCUU

GCUUGCCUU

CUUTGCCUUA

GUGGGAAUU

UGGGAAUuc CtJGAAACUA U CUUCUGGC.

C UUCUGGCU U CUGGCUCC C UGGCUCCU

CUUTCUUGU

J CLUGUCAU

:UUGTJCAUU

J GUCAUUGU -AUUGUCCtJ

JGUCCUACG

CUACGGAC

LCGGACCGU

rAAGCGGGC

*AGCGGGCC

*CUUCUA

*GUCUAUTUG

UALTUGUCA

UUGUCAUG

GUCAUGGA

AUGGAJCC

CAGAUGAA

GCCCLUUGG

GGAUGAGC

GCCUUAUG

AUGAUGCC

UGAUGCCA

CCCCAGGG

CCCAGGGA

GGAAAACC

135 2797 2799 2813 2814 2826 2839 2840 2841 2847 10 2863 2874 2880 2888 2917 2925 2930 2937 2943 2946 2949 2955 2959 2965 2967 2982 2985 3013 30152 3024

GCGGCCAA

CCGCGGCC

CUTJGGCCG

ACUUIGGCC

UCUGCCUC

AATUCCAA

CAAI~tJCCA

UCAAUUTCC

GUCUtJGUC UGtUUTUGC

UUTGACGGC

AACAUCUU

cUtUUUC

GAGGGCUC

UCAGACAU

UGAGUJCA

AGGAUCTU

UGGAUGAG

AUGUGGAU

CCAAUGUG

UGGUGACC

GAGAUGGU4

CACALUGA

kCCACALTU

.,CGCCUAG

7AGGCGCC 7ACCAUGA

WCACCAU

~aLUCCAC C CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X -UGAUGA X UGAUGA x =UAUGA x UTGAUGA x UJGAUGA X UGAUGA X GAA AGGCACCG GAA AAGGCACC GAA AUCACUUJG GAA AGCGUCUG GAA AAGCGUCU GAA AAAGCGUC GAA AUUCCAAA GAA AGUCGCUG .GAA ACUGUELJUU GAA ACGGCUAC GAA ACAUCUUG GAA AUGCUCGC GAA AGGGCUCG GAA ACAUGAGG GAA AGUUCAGA GAA AUCUUJGAG GAA AGGAUCUU GAA AUGAGGAU GAA AUGUGGAU GAA ACCAAUGU GAA AUGGUGAC GAA AGAUGGUG GAA AGGUUCAC 3AA AGGAGGUU 3AA AGGCCCUC 3AA AGAGGCCC .,AA AUCACCAU CUGAUGA X GAA AGGUUUUC CUGAUGA X GAA AGAGGULRU GAAAACCUC

IJUGGCCGC

AAACCUCUU

GGCCGCGG

CGGUGCCUU

CGGCCAAG

GGUGCCUUC

GGCCAAGU

CAAGUGAUJ

GAGOCAGA

CAGACGCUU UILJGGAAUU AGACGCUUU UGGAAUUG GACGCUUUU

GGAAUEJGA

UUUGGAAUU GACAAGAc CAGCGACUU

GCAAAACA

AAAACAGUA

GCCGUCAA

GUAGCCGUC

AAGAUGUJ

CAAGAUGUU

GAAAGAAG

GCGAGCAUC

GAGCCCUC

CGAGCCCUC

AUGUCUGA

CCUCAUGUC UGAACUCA UCUGAACUC

AAGAUCCU

CUCAAGAUC CtICAUCCA AAGAUCCUC

AUCCACAU

AUCCUCAUC CACAUUGG AUCCACAUU

GGUCACCA

ACAUEJGGUC

ACCAUCUC

GUCACCAUC

UCAAUGUG

CACCAUCUC AAUGUGGU GUGAACCUC

CUAGGCGC

AACCUCCUA

GGCGCCUG

GAGGGCCUC

UCAUGGUG

GGGCCUCUC

AUGGUGAU

AUGGUGAUU

GUGGAAUU

UGUGGAAUU CUGCAAGU 3032 ACUUGCAG CUGAUGA X GAA AUUCCACA 136 3033 3041

AACUELJGCA

GGUUIJCCA

3042 AGGUUUCC 3051 3053 3058 3059 3062 3063 10 3083 3084 3087 3088 3092 15 3094 3113 3114 3135 20 3144 3146 31541 3167 3177 3194 1 3203C 3209 C 3210

L

3213 UAAGtJUGA

AGUAAGU

CCGUAAGU

CCCGIJAAG

UGCCCCGU

UUGCCCCG

AGGGAACA

UAGGGAAC

UUAUAGGG

CUUAUAGG

UGCUCUJA

UUUGC.CU

CCUGGCGG

CCCUGGCG

CCCCAACG

AGCUCCCC

LCCACGGAC

GAUCCACGC

'JCUULItJCA C JGCuGucc c 'UGCUGGU C ~GCUGGCA C :AAAGCCU C ~CICAACA C JCCUCAAC C rucuccuc c CUGAUGA X GAA AAUUCCAC CUGAUGA X GAA ACUTJGCAG CUGAUGA X GAA AACUUGCA CUGAUGA X GAA AGGULUJCC CtJGAUGA X GAA AUAGGUUU CUGAUGA X GAA AGUUGAUA CUGAUGA X GAA AAGUUGAU CUGAUGA X GAA AGUAAGLU CUGAUGA X GAA AAGUAAGU CUGAUGA X GAZA AUtJCATU CUGAUGA X GAA AAUUCAUU CUGAUGA X GAA ACAAATJC "UGAUGA X GAA AACAAALTU 7UGAUGA X GAA AGGGAACA -UGAUGA X GAA AUAGGGAA :UGAUGA X GAA AGCGIJGCC 'UGAUGA X GAA AAGCGUGC UTGAUGA X GAA AGUCCULJG 'UGAUGA X GAA ACGUAGUC IUGAUGA X GAA AGCUCCCC 'UGAUGA X GAA AGAGCtJCC tJGAUGA X GAA AUCCACGG 'UGAUGA X GAZA AGCGUCU UGAUGA X GAA AUG CUGUC UGAUGA X GAA AGCUCUGG tIGAUGA X GAA AGCUGGCA (JGAUGA X GAA AGCCUGAG LJGAUGA X GAZA AAGCCUGA JGAUGA X GAA ACAAAGCC GUGGAZAUUC

UGCAAGUU

CUGCAAGUU

UGGAAACC

UGCAAGLTUU

GGAAACCU

GGAAACCUA

UCAACUTUA

AAACCUAUC

AACLTJACU

UAUCAACUU

ACLUJACGG

AUCAACUJIA CUtJACGGG AACUUACUU

ACGGGGCA

ACUJTACUUA

CGGGGCAA

AAAUGAAUU UGUtJCCCU AAUGAAUUU

GUUCCCUA

GAAUTUUGUU

CCCTJAUAA

AAUUUGUUC

CCUAUAAG

UGIJUCCCUA

UAAGAGCA

UUtCCCUAUA

AGAGCAAA

GGCACGCUU

CCGCCAGG

GCACGCtUC

CGCCAGGG

CAAGGACUA

CGUEJGGGG

GACUACGIJU

GGGGAGCU

GGGGAGCUC

UCCGUGGA

GGAGCUCUC

CGUGGAUC

CCGUGGAUC

UGAAAAGA

AAGACGCUU

GGACAGCA

GACAGCAUC

ACCAGCAG

CCAGAGCUC

UGCCAGCU

UGCCAGCUC

AGGCUUUG

CUCAGGCUU

UGUUGAGG

UCAGGCUUjj GUtJGAGGA GGCUUUGTUrU GAGGAGAA 3224 CACTJGAGC CUGAUGA X GAA AUUUCtJCC GGAGAAAUC GCUCAGUG 137 3228 ACAUCACU CUGATJGA X GAA AGCGAUUU 0 000* 0* 0 0 0* p 0000 0* p 00. 0 0 0000 0

P.O.

p p 0P p *000

P

0*00 3237 3253 3254 3266 3275 3276 3284 3292 10 3294 3297 3301 3302 3308 15 3309 3319 3332 333*3 33351 3341 3352 3354 3381C 3382 C 3384 L 3387t 3389 L 3405C 3406 A 3411A Ucu.Uccuc

IJUCUEJCAG

GIJUCUTUCA

AGUCCTJUG

AGGUCAGG

AAGGUCAG

GAUGCUCC

ACAGAUGA

UAACAGAU

CUGUAACA

GAAGCUGU

GGAAGCUG

CCACLTUGG

GCCACLTUG

CAUGCCCU

AUGCCAAG

GAUGCCAA

jtJGAIJGCC kcuucctuu MCUG1JGGAC JCCCUGUG

C

'AUAGGAGC

GAUAGGA

C

JCCGAUAGC

TJUCUCCGA

C

rcUUcuccC

AGAUCUUC

.CAGAUCU

C

AGUCACAC

CUGAUGA X GAA ACAUCACU CUGAUGA X GAA AGCUJCU CUGAUGA X GAA AAGCUUCU CUGAUGA X GAA ACAGUUCU CUGAUGA X GAA AGUCCUUG CUGAUGA X GAA AAGUCCItJ CUGAUGA X GAA AGGUCAGG CUGAUGA X GAA AUG CUCCA CUGAUGA X GAA AGAUGCUC CUGAUGA X GAA AIJGAGAUG CUGAUGA X GAA ACAGAUGA CUGAUGA X GAA AACAGAUG CUGAUGA X GAA AGCUGUAA CUGAUGA X GAA AAGCUGUA CUGAUGA X GAA AGCCACUU CUGAUGA X GAA ACUCCAUG -UGAUGA X GAA AACUCCAU 'UGAUGA X GAA AGAACUCC -7UGAUGA X GAA AUG CCAAG UGAUGA X GAA ACACUtJCC UGAUGA X GAA AUACACUEJ UTGAUGA X GAA AUGLJUUCG UGAUGA X GAA AAUGUUTUC UTGAUGA X GAA AGAAUGLU UGAUGA X GAA AGGAGAAU UJGAUGA X GAA AUAGGAGA IJGAUGA X GAA ACCACAUIJ UGAIJGA x GAA AAcC-AcAU UGAUGA X GAA AUCUAAC AAAUCGCUC

AGUGAUGU

AGUGAUGUA

GAGGAAGA

AAGAAGCUU

CUGAAGAA

AGAAGCUUC UGAAGAAc AGAACIJGUA

CAAGGACU

CAAGGACUTU

CCUGACCU

AAGGACUUC

CUGACCUU

CCUGACCUU

GGAGCAUC

UGGAGCAUC

UCAUCUGU

GAGCAUCUC

AUCUGUUA

CAUCUCAUC UGUtJACAG UCAIJCUGtJU

ACAGCUJC

CAUCUGTJUJA

CAGCUUCC

UUACAGCUU

CCAAGUGG

UACAGCUJC

CAAGUGGC

AAGUGGCUA

AGGGCAUG

CAUGGAGUU

CUUGGCAU

AUGGAGUtJC

UUGGCAUC

GGAGUUCUUI

GGCAUCAA

CUUGGCAUC

AAGGAAGU

GGAAGUGUA

UCCACAGG

AAGUGUAUC

CACAGGGA

CGAAACAUU

CUCCUAUC

GAAACAUUC

UCCUAUCG

AACAUtJCUC

CUAUCGGA

AUUCUCCUA

UCGGAGAA,

UCUCCUAUC

GGAGAAGA

AAUGUGGUU

AAGAUCUG

AUGUGGUUA

AGAUCUGU

GUUAAGAUC UGUGACUU 138 3419 CCAAGCCG CUGAUGA X GAA AGUCACAG b

OS

*0 0 0000 *4 9 9 00 S S 00.

*00* 0 .00 0 *I0* 09 0* 0 005* 9 0000 3420 3425 3438 3439 3440 3442 3454 3455 10 3459 3480 3484 3485 3510 15 3511 3512 3513 3522 3524 3531 3532 3548C 3550C 3551 P 3552 3560 C 3564A 3573A 3575C

GCCAAGCC

CCCGGGCC

UCUUUAUA

GtJCTUUAU GGUCUtJUA

CGGGUCUU

UCUGACAU

UUTCUGACA

CCUUUUCU

UIJCAAAGG

CCACUIJCA

UCCACIJUC

CUGUCAAA

UCUGUCAA

CIJCUGUCA

PLCUCUGUC

kULJGUGUA

GAALTUGUG

JCGCUCUG

kUCGCUCUC

ZACCGAAAC

:ACACCGAC

LCACACCG

C

LACACACC

C

*CCAGAGC

C

~ULUCCCA

C

AGGAAAA

UAAGGAA Cl CUGAUGA X GAA AAGUCACA CUGAUGA X GAA AGCCGAAG CUGAUGA X GAA AUGUCCCG CUGAUGA X GAA AAUGUCCC CUGAUGA X GAA AAAUGUCC CUGAUGA X GAA-AUAAAtJGU CUGAUGA X GAA AUCCGGGU CUGAUGA X GAA AAUCCGGG CUGAUGA X GAA ACAUAAUC CUGAUGA X GAA AGUCGGGC CUGATJGA X GAA AGGGAGUC CUGAUGA X GAA AAGGGAGU CUGAUGA X GAA AUGGTJC CtJGAUGA X GAA AAUGGUUUL CUGAUGA X GAA AAAUGGUUt ZUGAUGA X GAA AAAAUGGU UGAUGA X GAA ACUCUGUC 7UGAUGA X GAA AUACUCUG rnGAUGA X GAA AUULGUGUA UTGAUGA X GAA AAUUTGUGU UTGAUGA X GAA ACCACACA .UGAUGA X GAA AGACCACA UGAUGA X GAA AAGACCAC 'UGAUGA X GAA AAAGACCA UGAUGA X GAA ACACACCG UGAUGA X GAA AGCAACAC UGAUGA X GAA AUUIJCCCA LJGAUGA X GAA AUAtJUUCC CUGUGACUU

CGGCUUGG

UGUGACUUC

GGCUUGGC

CUUCGGCUU

GGCCCGGG

CGGGACAUU

UAUAAA.GA

GGGACAUJTU

AUAAAGAC

GGACAUUUA

UAAAGACC

ACAUUUAUA

AAGACCCG

ACCCGGAUU

AUGUCAGA

CCCGGAUUA

UGUCAGAA

GAUUAUGUC

AGAAAAGG

GCCCGACUC

CCUUUGAA

GACUCCCUU

UGAAGUGG

ACUCCCUUUJ

GAAGUGGA

GAAACCAUU

UUUGACAG

AAACCAJUtJ

UUGACAGA

AACC-AUUTUU

UGACAGAG

ACCAUUUUU

GACAGAGU

GACAGAGUA

UACACAAU

CAGAGUAUA

CACAAUUC

UACACAAUU

CAGAGCGA

ACACAAtJUC

AGAGCGAU

UGUGUGGUC

UUUCGGUG

UGUGGUCJT

UCGGUGUG

GUGGUCUUU

CGGUGUGU

tJGGUCUUUC

GGUGUGUU

CGGUGUGUUj

GCUCUGGG

GUGUUGCUC

UGGGAAAU

UGGGAAAUA

UUUTJCCUU

GGAAAUAUU

UUCCUUAG

GAAAUAUUU UCCUUAGG 3576 CCUAAGGA CUGAUGA X GAA AAUAUUUC 139 3577 ACCUAAGG CUGAIJGA X GAA AAAUAUUU 3578 3581 3582 3590 3596 3606 3612 3623 10 3624 3625 3628 3635 3649 15 3661 3668 3673 3686 3734 3737 3738 3739 3740 3746( 3757 3758C 3768 C 3803C 3805

CACCUAA

AGGCACCI

GAGGCAC

GGUAUGG(

CCCCAGG(

UCAAUCUI

UCLTUCAUC

UCCUACA7

CUCCUAC;

UCUCCUAC

CAAUCUCC

CUTJCUUUc

CCGCALUC

GUAGUCAG

GGGUAGUG

UUCUGGGG

UGGUCUGG

CtJGAAAAC

ACUCUGAA

k.ACUCUGA

CAACUCUG

:CAACUCU

3CUCCACC 3UUIUCCCA

;GUUUCCC

;CTUGCAG

;AACAAUA

LAGAACAA

G CUGAUGA LJ CUGAUGA

:CUGAUGA

3 CUGAUGA 3CUGAUGA J CUGAUGA 4 CUGAUGA

SCUGAUGA

iCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CTJGAUGA

CIJGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CTJGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA2

CUGAUGA

x x 2 2 x x x x x x x x x

K

.K GAA AAAAUAJU CGAA AGGAAAAU CGAA AAGGAAAA CGAA AGGCACCU CGAA AUGGGGAG GAA ACCCCAGG GAA AUCUUGAC GAA ATJTCUUCA GAA AAUTUCUU1C GAA AAAUUCUU GAA ACAAAAUU GAA AUCUCCUA GAA AGUUCCU GAA AGCCCGCA GAA AGUCAGGA GAA AGUGUAGU GAA ACAUtFJCU GAA AGGGUCUC GAA ACGAGGGU GAA AACGAGGG GAA AAACGAGG GAA AAAACGAG GAA ACUCUGAA GAA AUGCUCCA GAA AAUGCUCC GAA AGGUUUCC GAA AGUCUTJG GAA AUAGUCUU AAAUAUUUU

CCTJUAGGU

AAUAJIUtUC

CUUAGGUG

AUUUUCCUU

AGGUGCCU

UUUUCCUUA

GGUGCCUC

AGGUGCCUC

CCCAUACC

CUCCCCAUA

CCCUGGGG

CCUGGGGUC

AAGAUUGA

GUCAAGAUU

GAUGAAGA

UGAAGAAUU

UUGUAGGA

GAAGAAUUU

UGUAGGAG

AAGAAUJUU

GUAGGAGA

AAUUUTUGUA

GGAGAUUG

UAGGAGAtJU

GAAAGAAG

AAGGAACUA

GAATJGCGG

UGCGGGCUC

CUGACUAC

UCCUGACUA

CACIJACCC

ACUACACUA

CCCCAGAA

AGAAAUGUA

CCAGACCA

GAGACCCUC GTUttJCAG ACCCUCGLU U UCAGAGU CCCUCGUUU

UCAGAGJU

CCUCGIJUUU

CAGAGUUG

CUCGUUEJUC

AGAGUUGG

UTJCAGAGUU

GGUGGAGC

UGGAGCAUU

UGGGAAAC

GGAGCAUUTU

GGGAAACC

GGAA.ACCUC

CUGCAAGC

CAAAGACUA

UAUUGUEJC

AAGACUAUA

UUGUUCUU

GACUAUAULJ GUUCUUECC 3807 GGAAGAAC CUGAUGA X GAA AUAUAGUC 3810 AUUrGGAAG CUGAUGA X GAA ACAAUAUA 3811 3813 3814 3821 3847 3848 3855 3857 3865 3869 3876 3877 3878 3883 3914 3915 3919 39201 39391 3943 3946 3947 3949C 3951C 3961C 3987 3995 i 3996

CAUUGGAA

GACAUUGG

UGACAUUG

GUGUCUCU

GAGUCCAG

AGAGUCCA

GGCAGGGA

UAGGCAGG

AGGUGAGG

AAACAGGU

AUACAGGA

CAUACAGG

CCAUACAG

UTJCCUCCA

CAUAAUGG

UCAUAAUG

GUUGUCAU

LJGUUGUCA

LJAAUGACUC

3AGAUAAU -MtGGAGAUC

JCUGGAGAC

ULUCUGGAC

MnUEJCUG C UEJCGCU C LAUGUUUJ C FALCU CA C

,UAUCUUCC

CUGAUGA X GAA AACAAUAU CUGAUGA X GAA AGAACAAU CUGAUGA X GAA AAGAACAA CUGAUGA X GAA ACAUUGGA CUGAUGA X GAA AUCCUCUUJ CUGAUGA X GAA AAUCCUCU CUGAUGA X GAA AGUCCAGA CUGAUGA X GAA AGAGUCCA CUGAUGA X GAA AGGCAGGG CUGAUGA X GAA AGGUAGGC CUGAUGA X GAA ACAGGUGA CUGAUGA X GAA AACAGGUG CUGAUGA X GAA AAACAGGU CUGAUGA X GAA ACAGGA7A CUGAUGA X GAA AUUUGGGG CUGAUGA X GAA AAUUTJGGG 7UGAUGA X GAA AUGGAAUU 'UGAUGA X GAA AAUGGAAU 'TUGAUGA X GAA AUUCCUGC ~UGAUGA X GAA ACUGAUEJC UTGAUGA X GAA AUGACUGA UTGAUGA X GAA AAUGACUG .TUGAUGA X GAA AUAAUGAC ~UGAUGA X GAA AGAUAAUG 'UGAUGA X GAA ACUGUUCU UGAUGA X GAA ACACUCAC UGAUGA X GAA AUGUUUUU UGAUGA X GAA AAUGULUU UAUAUTUGUU CUUCCAAU AUAUUGtJUC

UUCCAAUG

AUUGUUCUU

CCAAUGUC

UtJGUUCUUC

CAAUGUCA

UCCAAUGUC

AGAGACAC

AAGAGGAUU

CUGGACUC

AGAGGAUUC

UGGACUCU

UCUGGACUC

UCCCUGCC

UGGACUCUC

CCUGCCUA

CCCUGCCUA

CCUCACCU

GCCUACCUC

ACCUGULU

UCACCUGUU

UCCUGIJAU

CACCTJGUUU

CCUGUAUG

ACCUGUUjC CUGIJAtGG UUUCCtJGUA

UGGAGGAA

CCCCAAAUU

CCALUTJAUG

CCCAAALUC

CALTJAUGA

AAUUCCAtJU

AUGACAAC

AUIJCCAtJUA

UGACAACA

GCAGGAAUC

AGUCAUUA

GAAUCAGUC

AUUIAUCUC

UCAGUCAUU

AUCUCCAG

CAGUCAUUA

UCUCCAGA

GUCAUUAUC

UCCAGAAC

CAUUAUCUC

CAGAACAG

AGAACAGUA

AGCGAAAG

GUGAGUGUA

AAAACAUU

AAAAACAUU

UGAAGAUA

AAAACAUTUU

GAAGAUAU

UUJGAAGAUA UCCCAUTUG 4003 CAAUGGGA CUGAUGA X GAA AUCuUCAA 141 4005 UCCAAUGG CUGAUGA X GAA ATJAUCUUC 0 000** 4010 4026 4035 4068 4071 4076 4093 4112 4113 4115 4117 4121 4123 4124 4125 4144 4157 4166 41751 4193 4199 4205 4207 4211 4235C 4238C 4257 4258C GLUJCCtJCC

AUCACLUUJ

UCAUCUGG

GAUGCAAG

UCIJGAUGC

GCUJUCU

GUCUtJCCA

AUGGAGAU

GAUGGAGA

AAGAUGGA

AAAAGAUG

CACCAAAA

UCCACCAA

UUCCACCA

AUJCCACC

CCUGCUU

AGGCCACA

1GCCUUCC

LJCUGGUUG

CAGACUGG

3AUACCCA

ZUGAGUGA

kUCUGAGUC

JGUCAUCUC

GCUGGAGC

~GUCGCUG

C

LUCUUUAA C

AUCUULJAC

CUGAIJGA X GAA AUGGGAUA CUGAUGA X GAA ACUUCUGG CUGAUGA X GAA AUCACUUU CUGAUGA X GAA ACCAUCCC CUGAUGA X GAA AGGACCAU CUGAUGA X GAA AUG CAAGG CUGAUGA X GAA AGUUUTJCA CUGAUGA X GAA AUUUGUUTC CUGAUGA X GAA AAUUUGtU CUGAUGA X GAA AUAAUUUG CUGAUGA X GAA AGAUAALU CUGAUGA X GAA AUGGAGAU CUGAUGA X GAA AGAUGGAG CUGAUGA X GAA AAGAUGGA CUGAUGA X GAA AAAGAUGG CUGAUGA X GAA ACUGGGCA CUGAUGA X GAA ACUCCCUG CUGAUGA X GAA AGGCCACA UGAUGA X GAA AGCCUUCC 7UGAUGA X GAA AGCCACUG 'UGAUGA X GAA ACUGGUAG UTGAUGA X GAA ACCCAGAC UTGAUGA X GAA AUACCCAG UTGAUGA X GAA AGUGAUAC 'TUGAUGA X GAA ACACGGUG :UGAUGA X GAA AGUACACG UGAUGA X GAA AGUCCUGC UGAUGA X GAA AAGUCCUG GAAGAUAUC

CCAUUGGA

UAUCCCAIJIJ

GGAGGAAC

CCAGAAGUA

AAAGUGAU

AAAGUGAUC CCAGAuGA GGGAUGGUC CUuGCAuc AUGGUCCUUJ

GCAUCAGA

CCUUGCAIJC

AGAAGAGC

UGAAAACUC

UGGAAGAC

GAACAAAUU

AUCUCCAU

AACAAAUUA

UCUCCAUC

CAAAUUAUC

UCCAUCUUJ

AAUUAUCUC

CAUCLUU

AUCUCCAUC

UUUUGGUG

CUCCAUCUU

IJUGGUGGA

UCCAUCUUTU

UGGUGGAA

CCAUCUUUTJ

GGUGGAAU

UGCCCAGUA

AAAGCAGG

CAGGGAGUC

UGUGGCCU

UGUGGCCUC

GGAAGGCU

GGAAGGCUC

CAACCAGA

CAGUGGCUA

CCAGTJCUG

CUACCAGUC

UGGGUAUC

GUCUGGGUA

UCACUCAG

CUGGGUAUC

ACUCAGAU

GUAUCACUC

AGAUGACA

CACCGUGUA

CUCCAGCG

CGUGUACUC

CAGCGACG

GCAGGACUIJ

UUAAAGAU

CAGGACUUTJ UAAAGAUG 4259 CCAUCUtJU CUGAUGA X GAA AAAGUCCU AGGACULUuU AAAGAUGG 142 4260 ACCAUCUU CUGAUGA X GAA AAA.AGIJCC GGACUtJUUA AAGAUGGU e 4281 4282 4292 4311 4316 4321 4322 4323 10 4336 4341 4348 4360 4369 4387 4388 4392 4393 43.94 4395 4402 4405( 4406C 4408 C 4409 C 4410 4425 4433 4434U 4438A

UCAGCGUG

GUCAGCGU

UGGUCCCU

CAGGAGGU

UJUAAACAG

UCCAUTUUA

UtJCCAJLJIJ

CUUJCCAUU

CGGGACAG

GGAGCCGG

UGGGGGCG

AtJUUCCAG

UCUCUCGU

GAAAAUCU

UGAAAAUC

CACUUtGAA

ACACUUTGA

kACACUG

CAACACUU

3AAAGAAC 3UGGAAAG 3GUGGAAA

;UGGUGGA

GIJGGIJGG

;GGUGGUG

C

LAUGUGGC

C

LAAAUCAC

rGAAAAIJC

C

AAAUGAAC

CUGAUGA X GAA ACUGCAGC CUGAUGA X GAA AACUGCAG CUGAUGA X GAA AGUCAGCG CUGAUGA X GAA AGCUGCAG CUGAUGA X GAA AGGUGAGC CUGAUGA X GAA ACAGGAGG CUGAUGA X GAA AACAGGAG CUGAUGA X GAA AAACAGGA CUGAUGA X GAA ACCACUUC CUGAUGA X GAA ACAGGACC CUGAUGA X GAA AGCCGGGA CUGAUGA X GAA AGUUGGGG CUGAUGA X GAA AUUUCCAG CUGAUGA X GAA AGCAGCAC CUGAUGA X GAA AAGCAGCA CUGAUGA X GAA"AUCUAAGC CUGAUGA X GAA AAUCUAAG CUGAUGA X GAA AA.AUCUAA CUGAUGA X GAA AAAAUCUA ZUGAUGA X GAA ACACUtJGA 7UGAUGA X GAA ACAACACU 'UGAUGA X GAA AACAACAC 'UGAUGA X GAA AGAACAAC -UGAUGA X GAA AAGAACAA UGAUGA X GAA AAAGAACA :UGAUGA X GAA ACUUCCGG TUGAUGA X GAA AUGUGGCU UGAUGA X GAA AAUGUGGC .UGAUGA X GAA AUCAAAUG

GCUGCAGU

CUGCAGLU

CGCUGACUi

CUGCAGCU(

GCUCACCU(

CCUCCUGUI

CUCCUGUUEI

UCCUGUUU]

GAAGUGGUC

GGUCCUGUC

UCCCGGCUC

CCCCAACUC

CUGGAAAUC

GUGCUGCUU

UGCUGCUUA

GCLUAGAUU

CUUAGAUtU

UUAGAUUUUJ

UAGAUUUTJC

UCAAGUGUU

AGUGLUUGLTEJ

GUGUUGUUC

GUUGUUCUU

UUGUTUCUUrJ

UGUUCUUUC

CCGGAAGUA

AGCCACAUU

GCCACAUUiJ

CAUUUGAUU

U CACGCUGA C ACGCUGAC

AGGGACCA

:ACCUCCUG

-CUGUUUAA

J UAAAUGGA J AAAUGGAA

AAUGGAAG

CUGUCCCG

CCGGCUCC

CGCCCCCA

*CUGGAAAU

ACGAGAGA

AGAUUUUC

GAUUUUCA

LUUCAAGUG

UCAAGUGU

CAAGUGUU

AAGUGUTUG

GUUCLTUtUC

CULUJCCAC

UIJUCCACC

UCCACCAC

CCACCACC

CACCACCC

GCCACALU

UGAUUULJC

GAUUUUCA

UUCATUUU

143 *5

S

S.

S

S

4439 4440 4441 4444 4445 4446 4447 4461 4477 10 4480 4483 4491 4492 4493 15 4525 4530 4532 4535 4537 4539 4540 4541 4542 4546 4547 4550 4551 4552 4558 4561

AAAAAUGA

CAAAAAUG

CCAAAAAU

CCUCCAAA

UCCUCCAA

CUCCUCCA

CCUCCUcC

UGCAGUCU

CUGAGGAC

GCCCUGAG

AAUGCCCU

UCUCUGGA

UUCUCUGG

CUUJCUCUG

GUAGAGUC

AGAGAGUA

AAAGAGAG

GGAAAAGA'

AUGGAAAA

GAAUGGAA

UGAAUGGA

AUGAAUGG

AAUGAAUG

UUUAAAUG

UUUJUAAAU

GACUUULUA

GGACUTUUC

AGGACUUU CJ

IJJAUAUAGC

PLCAULJAUA C CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAtJGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAIJGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X 7UGAUGA X 7UGAUGA X :UGAUGA X UJGAUGA X UJGAtJGA X XIGAUGA X :UGAUGA X GAA AAUCAAAU GAA AAAUCAAA GAA AAAAUCAA GAA AIJGAAAAU GAA AAUGAAAA GAA AAAUGAAA GAA AAAAUGAA GAA AGGUCCCU GAA AGCUCCUU GAA ACAAGCUC GAA AGGACAAG GAA AUG CCCUG GAA AAUGCCCU GAA AAAUGCCC GAA ACACAUUC GAA AGUCAACA GAA AGAGUCAA GAA AGUAGAGU GAA AGAGUAGA GAA AGAGAGUA GAA AAGAGAGU GAA AAAGAGAG GAA AAAAGAGA GAA AUGGAAAA GAA AAUGGAAA GAA AUGAAUGG GAA AAUGAAUG GAA AAAUGAAU 3AA ACUJUTJAA 3AA AGGACUU AUUUGAUTJU UCAUUUUtJ UtJUGAUUtJU

CAUUUUG

UUGAUEJUJUC AUUUUTJGG AULTrJUCATJU UUUGGAGG UUUUCAUtUU

UUGGAGGA

UUUCAIJUUU UGGAGGAG UUCAUUUUJ GGAGGAGG AGGGACCUC

AGACUGCA

AAGGAGCUU

GUCCUCAG

GAGCUUGUC

CUCAGGGC

CUU2GUCCUC

AGGGCAUEJ

CAGGGCAUEJ

UCCAGAGA

AGGGCAUUU

CCAGAGAA

GGGCAUJTUC

CAGAGAAG

GAA!JGUGUU

GACUCUAC

UGUUGACUC

UACUCUCU

UUGACUCUA

CUCUCUULJ

ACUCUACUC

UCUULTLJCC

UCUACUCUC UUtJUCCAU UACUCUCUU

UUCCAUTJC

ACUCUCUUU

UCCAUTUCA

CUCUCUIUUU CCAUtJCAU UCUCULUTC

CAUTJCAUU

UUUUCCAUU

CAIJTJEAAA

LUUCCAUtJC

AUUULAAAA

CCAUUCAUU

UAAAAGUC

CAUUCAUTUU

AAAAGUCC

AUUCAUUTUA

AAAGUCCU

LTUAAAAGUC

CUAUAUAA

AAAGUCCUA UAUAAUGU 4563 GCACAUUA CUGAUGA X GAA AUAGGACU 4565 4583 4585 4589 4595 4596 4609 4610 10 4611 4625 4629 4632 4654 4668 4683 4684 4691 4709 4722 4726 4728 4732 4740C 4741 t 4758t 4771 C 4772 C 4811C

GGGCACA

GGUAGUG

CUGGUAG'

UUAACUGi LTUUGCUU1I UIUUUtGCU1l

GUGUUUG)

CGUGLUJCJ

ACGUGUUL

GGAGGAC7

UCUUGGAC

ACUULCUULC

GtUUUCACP.

GCCCALTUC

AACACACA

CAACACAC

CCAUCCUC

GGCCCUGG

GGUAGACA

CCAAGGUA

MCCAAGG

!LAGCCUCC

:CUCCACA

JCCUCCAC

JUGGCUCA

~CACACUU

~CCACACU

UTCCGAGC

U CUGAUGA A. CUGAUGA UI CUGAUGA

SCUGAUGA

J CUGAUGA J CUGAUGA k. CUGAUGA

CUGAUGA

J CUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA)

CUGAUGA)

CUGAUGA

CUGAUGA CUGAUGA x CUGAUGA x CUGAUGA X x x x x x

'C

K GAA AUAUAGGA XC GAA ACCACAGC K GAA AGACCACA -K GAA AGUGAGAC CGAA ACUGGUAG

CGAA--AACUGGUA

GAA AGUCUULU GAA AAGUCU.U GAA AAAGUCUUJ GAA AGUCCACG GAA ACAGAGUC GAA AGGACAGA GAA AGGUGCCG GAA AUCCAGUU GAA AGCAUUGC GAA AAGCAUtJG GAA ACACACAA GAA ACAUCUCA GAA ACUCGGCC GAA ACAGACUC GAA AGACAGAC GAA AGGUAGAC GAA AGCCUCCA GAA AAGCCUCC GAA AGCCCGCA GAA ACACLUGG GAA AACACUUG GAA ACUUGCGC AGUCCUAUA

UAAUGUGC

UCCUAUAUA

AUGUGCCC

GCUGUGGUC

UCACUACC

UGUGGUCUC

ACUACCAG

GUCUCACUA

CCAGUUAA

CUACCAGULI

AAAGCAAA

UACCAGUUA

AAGCAAAA

AAAAGACUU

UCAAACAC

AAAGACUTUU

CAAACACG

AAGACUUUC

AAACACGU

CGUGGACUC

UGUCCUCC

GACUCUGUC

CUCCAAGA

UCUGUCCUC

CAAGAAGU

CGGCACCUC

UGUGAAAC

AACUGGAUC

GAAUGGGC

GCAAUGCUU

UGUGUGUU

CAAUGCUUU

GUGUGUUG

UUGUGUGUU

GAGGAUGG

UGAGAUGUC

CCAGGGCC

GGCCGAGUC

UGUCUACC

GAGUCUGUC

UACCUUGG

GUCUGUCUA

CCUUGGAG

GUCUACCUU

GGAGGCUU

UGGAGGCUTEJ

UGUGGAGG

GGAGGCUUJ

GUGGAGGA

UGCGGGCUA

UGAGCCAA

CCAAGIJGUU AAGUGtJGG CAAGUGUUA

AGUGUGGG

GCGCAAGUC GCUCGGAG 0 4815 CGCUCUCC CUGAUGA X GAA AGCGACUU AAGUCGCUC GGAGAGCG 145 4826 CAGGCUCC CUGAUGA X GAA ACCGCUCU AGAGCGGUU GGAGCCUG 4844 4854 4870 4880 4908 4909 4913 4914 10 4915 4923 4924 4932 4934 4935 4941 4946 4947 4957 4958 4969 4970 4971 4974 4977 4980 4989 49901 4993 4994

GCCAGCAC

CUCCACCA

CAGGCCAC

CGUUTJCCU

CAAAACCA

CCAAAACC

CCUUJCCAA

ACCUIJCCA

AACCtJUCC

AGCACGCA

GAGCACGC

ACUGUGAA

CGACUGUG

CCGACUGU

UGUAACCC

UCGCCUGU

CUCGCCUG

CCACAGGG

GCCACAGG

GAGUAGGA

GGAGUAGG

AGGAGUAG

AUUtAGGAG

CUCAULJAGC

kCUCUCAU

CCGGAAGGC

JCCGGAAGC

3AGUCCGGC kGAGUCCGC CUGAUGA X GAA AUGCAUCU CUGAUGA X GAA AGCCAGCA CUGAUGA X GAA AGCCCACC CUGAUGA X GAA ACAGGCCA CUGAUGA X GAA ACCCUGCC CUGAUGA X GAA AACCCUGC CUGAUGA X GAA ACCAAACC CUGAUGA X GAA AACCAAAC CUGAUGA X GAA AAACCAAA CUGAUGA X GAA ACCUtJCCA CUGAUGA X GAA AACCUUCC CUGAUGA X GAA AGCACGCA CUGAUGA X GAA AGAGCACG CUGAUGA X GAA AAGAGCAC CUGAUGA X GAA ACUGUGAA CUGAUGA X GAA ACCCGACU CUGAUGA X GAA AACCCGAC CUGAUGA X GAA ACUCGCCU CUGAUGA X GAA AACUCGCC CUGAUGA X GAA ACGCCACA -UGAUGA X GAA AACGCCAC =hAUGA X GAA AAACGCCA 7UGAUGA X GAA AGGAAACG 'UGAUGA X GAA AGUAGGAA UGAUGA X GAA AGGAGUAG UGAUGA X GAA ACUCUCAU UGAUGA X GAA AACUCUCA UTGAUGA X GAA AGGAACUC .UJGAUGA X GAA AAGGAACU

AGAUGCAUI

UGCUGGCU(

GGUGGGCMt

UGGCCUGUC

GGCAGGGUL

GCAGGGL

GGUUUGGULi

GUUJUGGUUC

UUUGGUUUUJ

UGGAAGGUU

GGAAGGUUU

UGCGUGCUC

CGUGCUCUU

GUGCUCUUC

UUCACAGUC

AGUCGGGUU

GUCGGGUJA

AGGCGAGU

GGCGAGUUTC

UGUGGCGUUI

GUGGCGUUU

UGGCGUUU2C

CGUIJCCUA

UUCCUACUC

CUACUCCUA

AUGAGAGUU

UGAGAGUUC

GAGUUCCUJ

AGUJCCUUjC J GUGCUGGC.

-UGGUGGAG

J GUGGCCUG

-AGGAAACG

JUGGTJUUUG

JGGUUUUGG

UT TJGGAAGG rUGGAAGGU

GGAAGGUU

UGCGUGCU

GCGTJGCUC

UUTCACAGU

CACAGUCG

ACAGUCGG

GGGUUIACA

ACAGGCGA

CAGGCGAG

CCCUGUGG

CCUGUGGC

UCCUACUC

CCUACUCC

CUACIJCCU

CUCCTJAAU

CUAATJGAG

AUGAGAGU

CCUUCCGG

CUTUCCGGA

CCGGACUC

CGGACUCU

a a 146 5001 ACACGUAA CUGAUGA X GAA AGUCCGGA 5003 AGACACG' 5004 5010 5012 5046 5050 5053 5054 10 5057 5060 5062 5064 5076 5077 5080 5081 5105 5116 5135 5156 5162 5163 5164 5203 5211 5212 5214 1 5218 C

GAGACACG

GGCCAGGA

CAGGCCAG

GAAGGAGC

UGAGGAAG

AGAUGAGG

GAGAUGAG

UGAGAGAU

GCCUGAGA

CAGCCUGA

CACAGCCU

UCUGAALU

UUCUGAAU

GUGUUCUG

GGUGLUJCU

CCUCUGCC

CCCGTJCAG

GUUCUCAC

GAAACCCU

CCAGCAGA

CCCAGCAG

kCCCAGCA kACCCUCAC

JGACAGAGC

JUJGACAGAC

~CU1JGACA C

GCCACUUC

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X -UGAUGA X UGAUGA XC UGAUGA XC UTGAUGA XC 'UGAUGA XC UTGAUGA X UTGAUGA xG ~UGAUGA XG ,TJGAUGA XG GAA AGAGUCCG GAA AAGAGUCC GAA ACACGUAA GAA AGACACGU GAA AGCUGCAU GAA -AGCAAGCU GAA AGGAGCAA GAA AAGGAGCA GAA AGGAAGGA GAA AUGAGGAA GAA AGAUGAGG GAA AGAGAUGA GAA AGGCACAG GAA AAGGCACA GAA AUULAAGGC GAA AATUAAGG 7AA ACGITJCCU .3AA AGCCUCUG 3AA ATJUCUUCG 'AA AGUUUCUG 'AA ACCCUGAG ;'AA AACCCUGA ,AA AAACCCUG 'AA ACCUGCCA 'AA ACCCUCAG A AACCCUCA AA AGAACCCU AA ACAGAGAA UCCGGACUC UUtACGUGU CGGACUCUU

ACGUGUCU

GGACUCULJA

CGUGUCUC

UTJACGUGUC

UCCUGGCC

ACGUGUCUC

CUGGCCUG

AUGCAGCUU

GCUCCUUC

AGCUUGCUC

CUUCCUCA

UUtGCUCCTUU

CCUCAUCU

UGCUCCUUC

CUCAUCUC

UCCUUCCUC

AUCUCUCA

UUCCUCAUC

UCUCAGGC

CCUCAUCUC

UCAGGCUG

UCAUCUCUC

AGGCUGUG

CUGUGCCLTL

AAIJUCAGA

UGUGCCUUA

AUUCAGAA

GCCUUAAUU

CAGAACAC

CCUUtAAUUC

AGAACACC

AGGAACGUC

GGCAGAGG

CAGAGGCUC

CUGACGGG

CGAAGAAUU

GUGAGAAC

CAGAAACUC

AGGGUTJUC

CUCAGGGUU

UCUGCUGG

UCAGGGUTUU

CUGCIJGGG

CAGGGUUUC

UGCUGGGU

UGGCAGGUC UGAGGGUtJ CUGAGGGUU

CUCUGUCA

UGAGGGUUC

UCUGTJCAA

AGGGUUCUC

UGUCAAGU

UUCUCUGUC

AAGUGGCG

GUGGCGGtJA AAGGCUCA 5229 UGAGCCUU CUGAUGA X GAA ACCGCCAC 147 5236 5247 5248 5250 5251 5254 5256 5258 5260 10 5265 5270 5283 5286 5290 5292 5293 5294 5295 5299 5300 5307 5308 5325 5327 5328 5331 5335

ACCAGCCU

AGAGGAAG

UAGAGGAA

GAUAGAGG

AGAUAGAG

UGGAGAUA

AGUGGAGA

GGAGUGGA

CAGGAGUG

CCUGACAG

GGGGGCCU

AUACUGAG.

AAAAUACU

AGCUAAAA

AAAGCUAA

CAAAGCUA

ACAAAGCU

CACAAAGC

AAGCCACA

GAAGCCAC

CCAUCAGG

GCCAUCAG

CCAALTUAA

AACCAAUU

CAACCAAU

AACCAACC

AGCAAACC

CUGAUGA X CUGAtJGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CtJGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X UGAUGA X GAA AGCCULTUA GAA ACACCAGC GAA AACACCAG GAA AGAACACC GAA AAGAACAC GAA AGGAAGAA GAA AGAGGAAG GAA AUAGAGGA GAA AGAUAGAG GAA AGUGGAGA GAA ACAGGAGU GAA ACUUGGGG GAA AGGACtJUG GAA ACUGAGGA GAA AUACUGAG GAA AAUACUGA GAA AAAUACUG GAA AAAAUACU GAA AGCUAAAA GAA AAGCUAAA GAA AGCCACAA GAA AAGCCACA GAA AUUUUUCU GAA AGAUUUUU GAA AAGAUUUU GAA AUUAAGAU 3AA ACCAAUUA 7AA ACCAACCA SAA AACCAACC 3AA AGCAAACC UAAAGGCUC

AGGCUGGU

GCUGGUGUU CU2UCCUCU CUGGUGUUC UUCCUCUA GGUGUUCUU CCUCUAUC GUGUUCUUC

CUCUAUCU

UUCUUCCUC UAUCUCCA CUUCCUCUA

UCUCCACU

UCCUCUAUC

UCCACUCC

CUCUAUCUC

CACUCCUG

UCUCCACUC CUGUCAGG ACUCCUGUC AGGCCCCC CCCCAAGUC CUCAGUAU CAAGUCCUC AGUAUUUUJ UCCUCAGUA LUUUAGCU CUCAGUAUTU

UTUAGCUUU

UCAGUAUJT UAGCUtJUG CAGUAUUU AGCUTUUGU AGUALUUTA

GCUUUGUG

LUUUJAGCUTU UGUGGCUU UUtJAGCUUU GUGGCUUC UUGUGGCUU CCUGAUGG UGUGGCUUC CUGAUGGC AGAAAAAUC

UUAATUGG

AAAAAUCUU AAUUGGUU AAAAUCUUA AUTUGGUUG AUCLTJAAUU GGUUGGUU UAALTJGGUU

GGUTUUGCU

UGGUUGGUU

UGCUCUCC

GGUUGGtJUU

GCUCUCCA

GGUUUGCUC UCCAGAUA 5339 GGAGAGCA 5340 5344 UGGAGAGC -CUGAUGA X UAUCUGGA CUGAUGA X 148 5346 AUUAIJCUG CUGAUGA X GAA AGAGCAAA a. a 5352 5355 5359 5367 5368 5369 5375 5376 10 5379 5380 5381 5382 5383 5392 5393 5398 5403 5405 5410 5412 5415 5416 5417 5422 54232 5424t 5425t 5430t 5432C

CUAGUGAU

UGGCUAGU

AAUCUGGC

AAUUIJCGA

UAAULUJCG

GUAAUUUC

IAAAAAGU

CLTAAAAAG

CGGCUAAA

UCGGCUAA

CIJCGGCUA

CCUCGGCU

ACCUCGGC

GUUAU CAU

UGUEJAUCA

GUAGAUGU

AUACAGUA

GGAUACAG

CUAAAGGA

ULJCUAAAG

kAALTUCUA kAAAUUCU

JAAAALTUC

JAGGUUAA

kUtAGGUUA JAtAGGUU C

IUJAUAGGUC

JAGUUUUA

C

:AUAGUUUr

C

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CtJGAUGA X CUGAUGA X CUGAtJGA X CUGAUGA X CUGAUGA X CUGAUGA x CUGAUGA X4 CUGAUGA x CUGAUGA X CUGAUGA X CUGAUGA x =JAUGA X 'UGAUGA XC UGAUGA XC UGAUGA XC UGAULGA XC UTGAUGA XC UGAUGA XC UGAUGA

X

GAA AUCUGGAG GAA AUUAUCUG GAA AGUGAUUA GAA AUCUGGCU GAA AAUCUGGC GAA AAAUCUGG GAA AUUUCGAA GAA AAUUUCGA GAA AGUAAUUUJ GAA AAGUAATJJ GAA AAAGUAAU GAA AAAAGUAA GAA AAAAAGUA GAA ACCUCGGC GAA AACCUCGG GAA AUCAUAAC GAA AUGUUAUC GAA AGAUGUUA 3AA ACAGUAGA 3AA AUACAGUA AA AGGAUACA 3AA AAGGAUAC 7AA AAAGGATJA ,AA AtJUCUAAA ,AA AAUUCUAA ;AA AAAUUCIJA ;AA AAAUUCU ;AA AGGUUAAA ,AA AUAGGUUA UUUtGCUCUC CAGAUAAU CUCCAGAUA

AUCACUAG

CAGAUAAUC

ACTJAGCCA

UAAUCACUA

GCCAGAUUJ

AGCCAGAUU

UCGAAAUU

GCCAGAtJUU

CGAAAUUA

CCAGAUUUC%'

GAAALTUAC

UUCGAAAtJU ACUUUUA UCGAAAtJUA

CUUEJUUAG

AAAUUACUEJ

UUUAGCCG

AAUUACUUU tJUAGCCGA AUUACUUUU

UAGCCGAG

UTUACUrUUUU

AGCCGAGG

UACUUUUUA

GCCGAGGU

GCCGAGGJU

AUGAUAAC

CCGAGGUUA

UGAUAACA

GUTUAUGAUA

ACAUCUAC

GAUAACAUC

UACUGIJAU

UAACAUCUA

CJGTJAUCC

UCUACUGUA UCCUtJUAG UACUGUAUC

CUUUAGAA

UGUAUCCUU

UAGAAUUU

GUAUCCUUtj AGAAUTUUU UAUCCUTUUA

GAALUUUA

UUtJAGAAUU

UUAACCUA

UTUAGAALUUJ

UAACCUAU

UAGAAUUUITU

AACCUAUA

AGAAUUUUA

ACCUAUAA

UEJUAACCUA

UAAAACUA

UAACCUAUA AAACUAUG 149 4 38 AGUAGACA CUGAUGA X GAA AGLUUAU 5442 AACCAGUA CUGAUGA X GAA ACAUAGU 5444 GAAACCAG CUGAUGA X GAA AGACAUAG 5450 CAGGCAGA CUGAIJGA X GAA ACCAGtJAG 5451 ACAGGCAG CUGALJGA X GAA AACCAGUA 5452 CACAGGCA CUGAUGA X GAA AAACCAGU AUAAAACUA UGUCUACU AACUAUGUC UACUGGUU CUAUGUCUA CUGGUUUC CUACtJGGUU UCUGCCUG UACUGGUUU CUGCCUGU ACUGGUUUC UGCCUGUG b* Where "IX" represents stem II region of a HH ribozyme (Hertel et al., 1992 Nucleic Acids Res. 20 3252). The length of stem II may be a 2 base-pairs.

0 ~0* 0 00 0e 0** 0** 00S S 0 *0 0.

0 00 0 00 0 00 0 0* 0 0 0 0 150 Table VII: Mouse Elk-1 VEGF Receptbr-Hairipjn Ribozyme and Substrate Sequences nt.

Posi.

tion 74 88 105 110 125 132 138 175 199 309 342 434 630 655 739 HP Ribozyme Sequence Substrate GGGCCCA GAC UGUGUCCC UCCCGCA GCC GGGAUAAC GGGACACA AGAA GGGCCC

ACCAGAGAAACACACGUUTGUGGUACAUACCUGGUA

GUUAUCCC

GGAAUCGG

UCCGCGGA

CGGCUGUC

CCAGCCC

CUGGCUCC

CAGCGCAA

GUCACAGA

CACAGAGC

CCCACAGA

UGCAAGUA

UAGACAUA

GAAUGGUG

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

A~GAA

GCGCGA

ACCAGAGAAACACACGUUTGUGGUACAUUACCUGGUA

GCCAGG

GGUCAG

GUGUCC

GUCAGC

GCGGCU

GGGGAG

GUAUGG

GCUAGC

GCUCGG

GAAGGG

GUGGAG

ACCAGAGAACACACGUGUGGUACAJLJACCUGGUA

ACCAGAGAAACACACGJTUGUGGUACAUU~ACCUGGUA

ACCAGAGAAACACACGUUrGUGGUACA1JUACCUGGUA ACCAGAGAAACACACGUUTGUGGUACAJUIACCUfGGUA

ACCAGAGAAACACACGJTUGUGGUACAJ.LACCUGGUA

ACCAGAGAAA.CACACGUUTGUGGUACAIYJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUULACCUGGUA

ACCAGAGAACACACGUUTGUGGUACAUACCUGGUA

ACCAGAGAAACACACGUUYGUGGUACAUUACCUGGUA

ACCAGAGAA.ACACACGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUACCUGGUA

ACCAGAGAAACACAGUUIGUGGUACAUACCUGGUA

CCUGGCU

CUGACCC

GGACACC

CCUGACA

AGCCGCG

CUCCCCG

CCAUACC

GCUAGCU

CCGAGCC

CCCUUCA

CUCCACU

GAUUACA

AUCCCCU

GAC

GAU

GCU

GCC

GCU

GUC

GCC

GUC

GCC

GAU

GUU

GAU

3CC CCGAUUtCC

UCCGCGGA

GACAGCCG

GCGGCUGG

GGAGCCAG

IJUGCGCUG

UCUGUGAC

GCUCUGUG

UCUGUGGG

UACUUGCA

UAUGUCUA

CACCAUUjC

GAGGGUCG

k.GAA GUAAUC CGACCCUC AGAA GGGGAU ACCAGAGAAACACACGUUrGUGGUACAUUACCUGGUA

S.

S

*SS

S

S S S S S S .5

S

S S S

SSS

S S S S S

S

too 55 5. 405 6. ve 90 00 0 too a 0 807 920 1002 1229 1365 1556 1629 1687 1696 1796 1950 1953 1985 2055 2082 2208 2252 2444 2639

CUGUUUCC

ACAUGAUA

UUUUc-cc

UCUUGAUC

AUAUCAGG

UCUCACCG

UUGGCGUA

UCUGUAGG

UUGGCCGG

UUCCUUCA

GGCUGGGC

GUUGGCUG

CAGUGCAC

CCCAUGUG

UtJCUUGCA

UUAUCUUG

GGAUGAUG

UGCGGAUA

GCUUAACG

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GGAACA

GAUAGG

GAUAGC

GUCCAC

GGGUAA

GGGGUG

GUGCAU

GGCUIUC

GUAGGA

GGGCAU

GGUUGC

GCAGGU

GGGACA

GAUGUU

GGUGUG

GAGCAA

GUUUGA

GGLJUCC

GUAGGA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUTUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

UGU1JCCG

CCUAUCA

GCUAUCU

GUGGACG

UUACCCA

CACCCCA

AUGCACA

GAAGCCU

UCCUACA

AUGCCCU

GCAACCU

AC CUG CU

UGUCCCU

AACAUCG

CACACCA

UUGCUCU

UCAAACA

GGAACCU

UCCUACG

GAU

GUC

GCC

GAU

GCU

GAU

GUC

GCU

GAC

GAU

GCU

GCC

GUU

GUC

GUU

GCU

GCU

GAC

GAC

GGAAACAG

UAUCAUGU

GGAGAAAA

GAUCAAGA

CCUGAUAU

CGGUGAGA

UACGCCAA

CCUACAGA

CCGGCCAA

UGAAGGAA

GCCCAGCC

CAGCCAAC

GUGCACUG

CACAUGGG

UGCAAGAA

CAAGAUAA

CAUCAUCC

UAUCCGCA

CGUUAAGC

0 152 2703 GGCAAUUC AGAA GGAUCC

ACCAGAGAAACACACGUJIGUGGUACAUTJACCUGGUA

GGAUCCA GAU GAAUUGCC 2777 2832 3199 3278 3304 3421 3450 3475 3663 3689 3703 3860 3873 4038 4181 4196 4212

CUAGUUTJC

CCAAAAGC

AAAGCCUG

GCUCCAAG

CACUUGGA

CCGGGCCA

CUGACAUA

CAAAGGGA

GUAGUGUA

CCAGCAUG

CUCAUGCC

GUGAGGUA

AUACAGGA

UGGCUGUC

AGCCACUG

GAUACCCA

UCUGUGUC

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

8,GAA kGAA kGAA kGAA

GGUCCC

GCCUCP

GGCAGA

GGAAGJ

GUAACA

GAAGUC

GGGUCU

GGCAUC

GGAGCC

GGUACA

GUCCAG

GGGAGA

GGUGAG

GGGAUC

GGUUGG

GGUAGC

GAGUGA

ACCAGAGAAACACAGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAJ1UACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAJTLACCUGGUA

ACCAGAGAAACACACGUUrGUGGUACAJTIACCUGGUA ACCAGAGAACACACAGUUTGUGGUACAUUrACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUrGUGGUACAJTUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUU1GUGGUACAUUTACCUGGUA ACCAGAGAAACACACGUrJGUGGUACAUUACCUGGUA ACCAGAGAAACACACGUUTGUGGUACAUUtACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUrJACCUGGUA

ACCAGAGAACACACAGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUrACCUGGUA

GGGACCG

UGAGGCA

UCUGCCA

ACIJUCCU

UGUIJACA

GACUUCG

AGACCCG

GAUGCCC

GGCUCCU

UGUACCA

CUGGACU

UCUCCCU

CUCACCU

GAUCCCA

CCAACCA

GCUACCA

UCACUCA

UGCUGCA

GC.

GAC

GCL

GAC

GCU

GCU

GAU

GAC

GAC

GAC

GCU

GCC

GUU

GAU

GAC

3AU

GAAACUAG

GCIJUUUGG

CAGGCUUU

CUUGGAGC

UCCAAGUG

UGGCCCGG

UAUGUCAG

01n

UCCCUUUG

UACACUAC

CAUGCUGG

GGCAUGAG

UACCUCAC

UCCUGUAU

GACAGCCA

CAGUGGCU

UGGGUAUC

GACACAGA

CACGCUGA

4278 UCAGCGUG AGAA GCAGCA

ACCAGAGAAA.CACACGJUGUGGUACAUUTACCUGGUA

.I

to 0 4287 GUCCCUGA AGAA GCGUGA ACCAGAGAAACACAGUU1GUGGUACAUUrACCUGGUA UCACGCU GAC UCAGGGAC 4307 4318 4338 4344 4349 4383 4462 4574 4626 4723 4823 4836 4896 4938 4996 5042 5118

AGGAGGUG

UCCAUUUA

GGAGCCGG

GGGGGCGG

GAGUUGGG

AAAAUCUA

UCCUUGCA

GAGACCAC

UCUUGGAG

CCAAGGUA

CAGGCUCC

CACAAUGC

ACCCUGCC

UGUAACCC

ACGUAAGA.

AAGGAGCA.

UCGGCCCC

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

PLGAA

AGAA

A.GAA

GCAGUG

GGAGGU

GGACCA

GGGACA

GAGCCG

GCACCU

GAGGUC

GGGCAC

GAGUCC

GACUCG

GCUCUC

GCAGGC

GCCUUU

GUGAAG

GGAAGG

GCAUCA

GGAGCC

ACCAGAGAAACACACGJT.GUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAACACACGUUrGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACG2JTGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

CACUGCA

ACCUCCU

UGGUCCU

UGUCCCG

CGGCUCC

AGGUGCU

GA C CUCA

GUGCCCU

GGACUCU

CGAGUCU

GAGAGCG

GCCUGCA

AAAGGCG

CUUCACA

CCUUCCG

UGAUGCA

GGCUCCU

GCU

GUU

GUC

GCU

CC

GCU

GAC

GCU

GUC

GUC

GUU

GAU

CC

GUC

GAC

GCU

CACCUCCU

UAAAUGGA

CCGGCUCC

CCGCCCCC

CCCAACUC

UAGAUUUU

UGCAAGGA

GUGGUCUC

CUCCAAGA

UACCUUCG

GGAGCCUG

GCALUGUG

GGCAGGGU

GGGUTUACA

UCUUACGU

UGCUCCUU

5165 CUCCACCC AGAA GAAACC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GGUUUCU GCU GGGUGGAG

C

C. C C C C C C C C C C C C. C C

C

0 154 5310 5363 545i UUUCUGCC AGAA GGAAGC ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA AUUtJCGAA AGAA GGCUAG ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA AGCACACA AGAA GAAACC ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA GCUUCCU GAU GGCAGAAA CUAGCCA GAU TJUCGAAAU GGUUUCU GCC UGUGUGCU 155 Table VIII: Mouse fit-i VEGE Receptor-Hammerhead Ribozyme and Substrate Sequence nt.

Posi HH Ribozyme Sequence Substrate tion 17 19 23 32 10 53 60 61 71 15 78 83 84 86 94 100 106 112 113 132 133 134 152 171 173 175 176 177

GUGAGCAP

UGGUGAGC

ACCAUGGU

CAGCAGCU

UAAGGCAA

CGUAAGGC

CAGCGCGU

GCAGCGCG

AGACACCC

GAGAAGCA

CCUGUGAG

UCCIJGUGA

UAUCCUGU

CUGAGCCA

UCGACCCU

UUAACUUC

GCACUUU

GGCACIUU

GCCUUULUA

UGCCUUULJ

GUGCCtUUU

GCUUGCAU

GAGAAAGA

UUGAGAAA

ACUtJGAGA

CACUUGAG

GCACULJGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

GAA ACGCGGCC GAA AGACGCGG GAA AGCAAGAC GAA ACCAUGGU GAA ACCGCGGU GAA AGACCGCG GAA AGGCAAGA GAA AAGGCAAG GAA AGCAGCGC GAA ACACCCGA GAA AGCAGACA GAA AAGCAGAC GAA AGAAGCAG GAA AUCCUGUG GAA AGCCAUAU GAA ACCCUGAG GAA ACUUCGAC GAA AACUUCGA GAA ACUCAGUU GAA AACUCAGU GAA AAACUCAG GAA ACAUGCUG GAA AGUCUGGC GAA AGAGUCUG GAA AGAGAGUC GAA AAGAGAGU GAA AAAGAGAG

GGCCGCGUC

CCGCGUCUI.

GIJCUUGCUC

ACCAUGGUC

ACCGCGGUC

CGCGGUCUJ

UCUTUGCCUU

CtJUGCCUUA

GCGCUGCUC

UCGGGUGUC

UGUCUGCJUU

GUCUGCUUC

CUGCUUCUC

CACAGGAUA

AUAUGGCUC

CUCAGGGUC

GUCGAAGUU

UCGAAGUUA

AACUGAGUU

ACUGAGLTUtJ

CUGAGUUTUA

CAGCAUGUC

GCCAGACUC

CAGACUCUC.

GACUCUCLU

ACUCUCUUU

CUCUCUUUC

'UUGCUCAC

JGCUCACCA

ACCAUGGU

AGCUGCUG

UUGCCUUA

GCCUUACG

ACGCGCUG

CGCGCUGC

GGGUGUCU

UGCUUCUC

CUCACAGG

UCACAGGA

ACAGGAUA

UGGCUCAG

AGGGUCGA

GAAGIJUAA

AAAAGUGC

AAAGUGCC

UAAAAGGC

AAAAGGCA

AAAGGCAC

AUGCAAGC

UCUUUCU.C

UUUCUCAA

UCUCAAGU

CUCAAGUG

UCAAGUGC

156 179 CUGCACUU CUGAUGA X GAA AGAAAGAG CUCUUUCUC AAGtJGcAG 205 211 213 254 258 265 282 292 293 304 310 341 343 15 351 355 359 363 367 369 372 373 394 396 397 401 403 407 409 410 413 414 GAGACC2

UGGGCAC

CGUGGGC

GGGGGAC

CGAUGGC

CACAGGC

UUGCCUG

UGCUGCA

GUGCUGC

CCAAGGU

CCGUGUC

CAGGUGU

UACAGGU(

GAGGUAU(

UAGGGAG(

GAUGUAGC

AGUAGAUC

UCGAAGuAz

CUUCGAAG.

UUUCUUCG

UUUUCtIEC

AGAUUGAA

GUAGAUUG

UGUAGAUU

AAUAUGUA

CAAAUAUG

CUAACAAA

CACUAACA

UCACUAAC

GCAUCACU

UGCAUCAC

WU CUGAUGA 'A CUCAUGA IA CUGAUGA ;U CUGAUGA ;G CUGAUGA 'C CUGAUGA U CUGAUGA G CUGAUGA A CUGAUGA C CUGAUGA

CUGAUGA

k~ CUGAUGA: 3 CUGAUGA

CUGAUGA

3CUGAUGA)

CUGAUGA)

CUGAUGA x LCUGAUGA x CUGAUGA X CUGAUGA X CUGAUGA

X

CUGAUGA

X

CUGAUGA x CUGAUGA X CUGAUGA x CUGAUGA x CUGAUGA X CUGAUGA

X

CUGAUGA x CUGAUGA x CUGAUGA x X G X GI X GI~ X G.P X GA1 X GA X GA X GA X GA X GA.

K GA 4 K GAJ C GP)

CGA)

GA7

GA-T

GAP

GAA

GA1A

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

k.A AGUGGGCU

~ACCAUGAG

~AGACCAUG

LAUGCUCAG

AAGUGAUGC

AAUGGGGGA

AAUCCCUCC

AAULJGCCUG

AAAUUGCCU

~AGGUGCUG

~AGGUCAAG

~AGGCCCGU

SAGAGGCCC

~ACAGGUGU

SAUCUACAG

AGGUAUCU

AGGGAGGU

AUGUAGGG

AGAUGUAG

A.GUAGAUG

AAGUAGAU

AUUCCGCU

AGAUUCCG

AAGAUUCC

AUUGAAGA

AGAUUGAA

AUGUAGATJ

AUAUGUAG

AAUAUGUA

ACAAAUAU

AGCCCAat

CUCAUGGL

CAUGGUCT

CUGAGCAU

GCAUCACU

UCCCCCAU

GGAGGGAU

CAGGCAAU

AGGCAAUUi

CAGCACCUI

CUUGACC~n

ACGGGCCU(

GGGCCUCUI

Ac-ACCUGU;z

CUGUAGAUP

AGAUACCUC

ACCUCCCUA

CCCUACAUC

CUACAUCUA

CAUCUACUU

AUCtJACUUC

AGCGGAAUC

CGGAAtJCUU

GGAAUCUUC

UCUUCAAUC

UTUCAAUCUA

AUCUACAUA

CUACAUALU

UACAUAUJU

AUAUUUGUU

UAUUUGUUA

IJC

AUGGUCUC

TC UCUGCCCA rc UGCCCACG IC ACUCCCCC 'C CCCCAUCG C GOCCUGUG A ACAGGCAA, LI CUGCAGCA 2UGCAGCAC J GACCUUTGG J GGACACGG

:UACACCUG

CACCUGUA

GAUACCUC

LCCUCCCUA

CCUACAUC

CAUCUACU

UACUEJCGA

CUUCGAAG

CGAAGAAA

GAAGAAAA

LTUrCAAUCU

CAAUCUAC

AAUCUACA

UACAUAUUI

CAUAUUUG

UUUGUUAG

UGUUAGUG

GUUAGUGA

AGUGAUGC

429 UAUGAAAG CUGAUGA X GAA ACUCCCUG CAGGGAGUC CUUUCAUA 157 432 433 434 43.7 455 464 491 494 497 10 514 524 530 536 544 15 545 546 550 551 555 20 558 560 561 581 594 604 605 606 608 611 625 635 662

CUCUAUG,

UCUCUAU

AUCUCUAI

UGCAUCU(

AGUUUGG(

AUGUGCA(

GGGAUGAT

CAGGGGAI

CGGCAGGC

CGUIJGGGL

GUGACUGL

UUTJAGGGJ

AACUUUUU

CAAAUGGA

UCAAAUGG

AUCAAAUG

GAGUAUCA

AGAGUAUC

GGUAAGAG

AGGGGUAA

UCAGGGGU

AUCAGGGG

UCCCAUGU

GCCUCUCC

CUAUUAUA

GCUAUUAU

UGCUAUUTA

UTUUGCUAU

GCAUUUGC

UCUCUUUG

AGCAGUCC

UGCCCGU

P, CUGAUGA 37 CUGAUGA J3 CUGAUGA 7CUGAUGA 3CUGAUGA

CUGAUGA

JCUGAUGA

JCUGAUGA

;CUGAUGA

T CUGAUGA rCUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA Y CUGAUGA y CUGAUGA N CUGAUGA x CUGAUGA X

GAI

GA7Z

GA]

GA;

GAP

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GA

Gk

G,

GAj

GA)

GA

AGGACUCC

~AAGGACUC

~AAAGGACU

SAUGAAAGG

~AUGUCAGU

\AGUUJGGG

'AGCUGUCU

AUGAGCUG

AUGAUGAG

ACGUCACC

ACGUUGGG

ACUGUGAC

AGGGUGAC

*ACUUUUUU

*AACUUUUU

*AAACUULU

AUGGAAAC

AAUGGAAA

AUCAAAUG

AGUAUCAA

AGAGUAUC

AAGAGUAU

ALTUCUUUG

ACUGUCCC

AGCCUCUC

AAGCCUCU

AAAGCCUC

AUAAAGCC

AUUAUAAA

ACGTJUGCA

AUCUCUUU

ACGGUGGC

GGAGUCCU1I

GAGUCCUUI

AGUCCUUJ(

CCUUUCAU)

ACUGACAUI

CCCAAACTL

AGACAGCJC

CAGCUCAUC

CUCAUCAUC

GGUGACGUC

CCCAACGUC

GUCACAGUC

GUCACCCUA

AAAAAAGtU

AAAAAGUUU

AAAAGUUUC

GUUUCCAtJLj

UUUCCAUUU

CAUUTUGAUA

TJUGAUACUC

GAUACUCUU

AUACUCUUA

CAAAGAAUA

GGGACAGUA

GAGAGGCUU

AGAGGCULU

GAGGCUUJA

GGCUUUAUA

UUUAUAAUA

UGCAACGUA

AAAGAGAUA

GCCACCGUC

J UCAUAGAG J CAUAGAGA

-AUAGAGAU

k~ GAGAUGCA k CCCAAACU

JGUGCACAU

AUCAUCCC

AUCCCCUG

CCCUGCCG

ACCCAACG

ACAGUCAC

ACCCUAAA

AAAAAGUU

UCCAtJUUG

CCAUUUGA

CAUUUGAU

UGAUACUC

GAUACUCU

CUCUUACC

UTUACCCCU

ACCCCUGA

CCCCUGAU

ACAUGGGA

GGAGAGGC

UAUAAUAG

AUAAUAGC

UAAUAGCA

AUAGCAAA

GCAAAUGC

CAAAGAGA

GGA CUGCU

AACGGGCA

676 UUGUCUGG CUGAUGA X GAA ACAGGUGC GCACCUGUA CCAGACAA 158 688 GGGUCAGA CUGAUGA X GA a a. a a a a 690 699 711 716 719 725 731 758 10 771 773 776 779 803 15 807 831 832 840 849 20 859 861 863 875 888 889 904 905 914 915 .917 918 923

AUGGGIJC

GGUCUGC

UAGGALU

ACAUCUA

UGGACAU

CGUAUUtJ

GGCGGGC(

UGCCCGU(

GAGGACA2

UUIGAGGA(

CAGUUGAC

GUGCAGUL

CUCGUAUL

CACCCUCC

ACCAGGG U

UACCAGGG

AGUUGCUU

UGCUCUCU

GCCtJUAUA

CUGCCUUA

CGCUGCCU

CUCCGGUC

GLUGUGGG

UGUUGUGG

CACUGUGG

ACACUGUG

AUCUUAAG

GAUCUUAA

UUGAUCUU

GUUTGAUCU

ACAUUGLU

A CUGAUGA C CUGAUGA

G-CUGAUGA

G CUGAUGA C CUGAUGA 3; CUGAUGA 3 CUGAUGA 3 CUGAUGA k CUGAUGA

CUGAUGA

CUGAtJGA

ICUGAUGA

TCUGAUGA

CUGAUGA

CUGAUGA

CUGAtIGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA)

CUGAUGA i) CUGAUGA x~ CUGAUGA x~ CUGAUGA X CUGAUGA X CIJGAUGA X CUGAUGA X CUGAUGA x CUGAUGA X CUGAUGA X 2 2 x

K

C

C

X GA X GA X GA X GA X GA X GAK K GAj K GA)

CGAI

CGA)

CGA;

GA)

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

AAGUUUGUC

AAUAGUUUG

AAUGGGUCA

AAUUGGUCU

PALTUGUAUU

~AGGAUUGU

~ACAUCUAG

SAUUUGGAC

SAGCAGUCU

~AGUCUGCC

~AGAGUCUG

ACAAGAGU

AGGACAAG

AGCUCCGU

AUUGAGCU

AUUCCAGC

AATTCCAG

ACCAGGGU

AGUUGCUU

AUGCUCUC

AGAUGCUC

AUAGAUGC

AUCCGCUG

AUGGCUCC

AAUGGCUC

ACACAUUG

AACACAUU

ACACUGUG

AACACUGU

AGAACACU

AAGAACAC

AUCUUAAG

GACAAACt CAAACUAt UGACCCAt

AGACCAAL

AAUACAATJ

ACAAUCCU

CUAGAUGU

GUCCAAAU

AGACUGCU

GGCAGACTJ

CAGACUCU

ACUCUTUGUi

CUUGUCCU(

ACGGAGCUC

AGCUCAAU)

GCUGGAAMt

CUGGAAUI

ACCCUGGUI

AAGCAACUP

GAGAGCAUC

GACCAUCU.A

GCAUCUAUA

CAGCGGAUU

GGAGCCAUU

GAG CCAUUC

CAAUGUGUTJ

AAUGUGUUC

CACAGUGUTJ

ACAGUGUUC

AGUGUUCtU GUGUtJCUUJA

CUUAAGAUC

JA UCUGACCC IC UGACCCAU IC GGCAGACC FA CAAUCCUA IC CUAGAUGU A GAUGUCCA C CAAAUACG A CGCCCGCC C CACGGGCA C UUGUCCUC LJ GUCCUCAA

CUCAACUG

AACtJGCAC 7 AAUACGAG k. CGAGGGUG

JACCCUGGU

CCCUGGUA

AAGCAACU

AGAGAGCA

UAUAAGGC

UAAGGCAG

AGGCAGCG

GACCGGAG

CCCACAAC

CCACAACA

CCACAGIJG

CACAGUGU

CUUAAGAU

UUAAGAUC

AAGAUCAA

AGAUCAAC

AACAAUGU

953 CAGGUGUA CUGAUGA X GAA AGCCCCUU AAGGGGCUC UACACCUG 159 .00:.

*.00.

00*0.

.*of: 955 963 979 982 985 986 991 993 994 10 995 1003 1015 1027 1028 1031 1044 1084 1087 1089 1096 1114 1115 1120 1130 1133 1138 1139 1150 1162 1168 1173 1177 1179

GACAGGUCG

CUUCACGC

GGAACGAG

ACUGGAAC

AAGACTJGG

AAAGACUG

UGUtJGAAA

GGUGUUGA

AGGUGUTUG

GAGGUGUU

CAUGCACG

CUUUtJUCA

CACUGAUG

ACACUGAU

UUCACACU

CUGCUUCC

GCCGAUAG

ACAGCCGA

GGACAGCC

CUUTUCAUG

GGGAGGGG

GGGGAGGG

UUUCUGGG

AACCAUAC

UTJUAACCA

CAUCTJUUU

CCAUCUUU

UUGCAGGC

CAGACUUC

AGCGAGCA

CAAAUAGC

GUACCAAA

AUGUACCA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA

GAA AGAGCCCC GAA ACAGGUGU GAA ACCCACUC GAA AGGACCCA GAA ACCAGGAC GAA AACGAGGA GAA ACUGGAAC GAA AGACUGGA GAA AAGACUGG GAA AAAGACUG GAA AGGUGUUG GAA ACACAUGC GAA AUCCULUU GAA AAUCCUUU GAA AUGAAUCC GAA AUGUUUCA GAA ACCGUCUU GAA AGGACCGU GAA AUAGGACC GAA ACAGCCGA GAA AGGCCUUC GAA AAGGCCUU GAA AGGGGAAG GAA AUUUCUGG GAA ACGAUUUC GAA ACCAUACG GAA AACCAUAC GAA AGCCAUCU GAA AUGUUGCA GAA ACUUCAAU GAA AGCAGACU GAA AGCGAGCA GAA AUAGCGAG

GGGGCUCUP

ACACCUGUC

GAGUGGGUC

UGGGUCCUC

GUCCUCGUL

UCCUCGUUC

GUIJCCAGUC

UCCAGUCUU

CCAGUCUUU

CAGUCUUUC

CAACACCUC

GCAUGUGUA

AAAAGGAUUJ

AAAGGAUTUC

GGAUUCAUC

UGAAACAUC

AAGACGGUC

ACGGUCCUA

GGUCCUAUC

UCGGCUGUC

GAAGGCCUU

AAGGCCUUC

CUUCCCUC

CCAGAAAUC

GAAAUCGUA

CGUAUGGLU

GUAUGGUUA

AGAUGGCUC

UGCAACAUUI

AUUGAAGUC

AGUCUGCUC

UGCUCGCUA

CUCGCUAUU

CACCUGUC,

GCGUGAAG

CUCGUUCC

GUUCCAGU

rCCAGUCUU

CAGUCLUU

UUUCAACA

UCAACACC

CAACACCU

AACACCUC

CGUGCAUG

UGAAAAAG

CAUCAGUG

AUCAGUGU

AGUGUGAA

GGAAGCAG

CUAUCGGC

UCGGCUGU

GGCUGUCC

CAUGAAAG

CCCCUCc cCUcc

CCCAGAAA

GUAUGGUU

UGGUUAAA

AAAAGAUG

AAAGAUGG

GCCUGCAA

GAAGUCUG

UGCUCGCU

GCUAUUUG

UUULGGUAC

UGGUACAU

160 0 1 1180 CAUGUACC CUGAUGA X GAA AAUAGCGA UCGCUAUTUU GGUACAUG.

0* 0* 1184 1192 1195 1198 1199 1202 1203 1205 1237 1239 1244 1246 1256 15 1264 1271 1273 1274 1275 20 1283 1293 1295 1298 1301 1314 1319 1321 1330 1336 1339 1343 1344 135S6

UAGCCAU

UUAAUGA

UAAUUAA

UGAUAAU

UUGAUAAI

UCUUUGAI

AUCUUUGJ

ACAUCUUI

AGAUCGUI

CAAGAUC(

CCCAGCAZ

UGCCCAGC

GACUGCUL

AUAGCCTJL

UUUUUAAA

GGUUUTUUA

AGGLUUUU

GAGGUUUU

GUGGCAGU

UACAAUGA

UtJUACAAU

ACGUUUAC

UUCACGLU

GUAGAUCU

UUUUCGUA

ACUUUtUCG

AGGACACG

GAAGCGAG

UUGGAAGC

GGGCUUGG

UGGGCUUG

CGGAUAGA

'G CUGAUGA G CUGAUGA U CUGAUGA U CUGAUGA UJ CUGAUGA J3 CUGAUGA

CUGAUGA

J CUGAUGA k. CUGAUGA

;CUGAUGA

SCUGAUGA

CUGAUGA.

TCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA i CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA 2 CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X X GAA ACCAAAUA X GAA AGCCAUGU X GAA AGUAGCCA K GAA AUGAGUAG K GAA AAUGAGUA K GAA AUTUAAUGA GAA AAUUAAUG CGAA AUAAUUAA I GAA AGUCCCCU 'GAA AUAGUCCC 'GAA AUCGUAUA GAA AGAUCGUA GAA AUGCCCAG GAA ACUGCUUU GAZA AGCCUTJGA GAA AUAGCCUU GAA AAUAGCCU GAZA AAAUAGCC GAA AGGUUUUU GAA AGUGOCAG GAA AGAGUGGC GAA AUGAGAGU GAA ACAZAUGAG GAZA AGGUUJECA GAA AUCUGAGG GAA AGAUCUGA GAA ACUUTUCG GAA ACACGGAC GAZA AGGACACG GAA AGCGAGGA GAA AAGCGAGG GAA AGGUGGGC

UAUUUGGU

ACAUGGCU

UGGCUACU

CUACUCAU

UACUCAULL

UCALTrJAAUJI

CAUUAAUU)

UUAAUUAU(

AGGGGACUJz

GGGACUAUJ

UAUACGAUC

UACGAUCUL

CUGGGCAUP

AAAGCAGUC

UCAAGGCtJA

AAGGCUAUU

AGGCUAUUJ

GGCUAUUULA

AAAAACCUC

CUGCCACUC

GCCACUCLJC

ACtJCUCAUJ

CUCAUTJGUA

UGAAACCUC

CCUCAGAUC

UCAGAUCUA

CGAAAAGUC

GUCCGUGUC

CGUGUCCUC

UCCUCGCUU

CCUCGCUTUC

GCCCACCTJC

A CAUGGCuA A CUCAUJTAA C AUUAAUIJA UJ AATJUAucA

AUUAUCAA

J AUCAAAGA

'UCAAAGAU

:AAAGAUGU

kUACGAUCU

CGAUCUUG

UUGCUGGG

GCUGGGCA

,AAGCAGUC

AAGGCUAU

UUUAAAAA

UAAAAACC

AAAAACCU

AAAACCUC

ACUGCCAC

UCAUTUGUA

AUUGUAAA

GUAAACGU

AACGUGAA

AGAUCUAC

UACGAAAA

CGAAAAGU

CGUGUCCU

CUCGCUUrC

GCUUCCAA

CCAAGCCC

CAAGCCCA

UCUZAUCCG

&S.0' Oee **toS 1358 1360 1362 1382 1385 1389 1399 1406 1410 1421 1430 1443 1452 1456 15 1468 1474 1475 1495 14-98 1499 1500 1502 1509 1522 1523 1535 1544 1546 1548 1562 1565 1578

AGCGGAU,

CCAGCGG,

GCCC-AGC(

CAAGUGA(

GUGCAAGI

CACGGUG(

GGAUGCC0

GGCCGAGC

UGUU.GGCC

AGCCACGL

GGGUGCCP

AUtJGUGGL UUtJGGAGU

LUUCUUUG

AGAAGUCA

CAGUGCAG

UCAGUGCA

GGAUAAAG

CCAGGAUA

UCCAGGAU

AUCCAGGA

GGAUCCAG

GCUGCUGG

UGUJEUCCU

CUGUUUCC

AUGCUCUC

CGCUGAGA

UGCGCUGA

CAUGCGCU

CCUUCUAU

GUuccuujc

AACCGUCU

kCUGAUGA k. CUGAUGA 3CUGAUGA 3 CUGAUGA J CUGAUGA

CUGAUGA

k. CUGAUGA

CUGAUGA

CUGAUGA

J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

*CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA2 CUGAUGA2 CtJGAUGA)

CUGAUGA

CUGAUGA

CUGAUGA Y CUGAUGA y CUGAUGA Y CUGAUGA N

IGA-

GA7

GAP

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GA

.GAJ

GA2

GA;

GA7

AGAGGUGG

SAGAGAGGU

~AUAGAGAG

'ACUUGUCU

SAGGACUUG

~AGTJGAGGA

ACACGGUG

AUGCCAUA

AGGGAUGC

AUUGUUGG

AGCCACGU

ACAGGGGU

*AUUGUGGU

*AGUGAUUG

ACCUtJUCU

AGUCAUAC

AAGUCAUA

AUUCUUCA

AGGAUTUCU

AAGGAUUC

AAAGGAUU

AUAAAGGA

AUCCAGGA

AGUTUGCJG

AAGUULGCU

AUUCUGtU

AUGCUCUC

AGAUGCUC

AGAGAUGC

ACCGUCAU

AUGACCGU

AUULUGUULC

CCACCUCU

ACCUCUCU

CUCUCUAU(

AGACAAGU(

CAAGUCCUC

UCCUCACUT.

CACCGUGU;

UAUGGCAUC

GCAUCCCUC

CCAACAAUC

ACGUGGCUC

ACCCCUGUC

ACCACAAUC

CAAUCACUC

AGAAAGGUA

GUAUGACUU

UAtJGACUtJC

UGAAGAAUC

AGAAUCCUU

GAAUCCUU

AAUCCUUUA

UCCUUUAUC

UCCUGGAUC

CAGCAACUU

AGCAACUUA

AACAGAAUU

GAGAGCAUC

GAG CAUCUC

GCAUCUCUC

AUGACGGUC

ACGGUCAUA

GAACAAAUA

:UAUCCGCU

k. UCCGCUGG

CGCUGGGC

:CUCACUUG

ACUtJGCAC J GCACCGUG

UGGCAUCC

CCUCGGCC

7GGCCAACA

ACGUGGCU

UGGCACCC

*ACCACAAU

*ACUCCAAA

CAAAGAAA

UGACUUCU

CUGCACUG

UGCACUGA

CUUIJAUCC

UAUCCUGG

AUCCUGGA

UCCUGGAU

CUGGAUCC

CCAGCAGC

AGGAAACA

GGAAACAG

GAGAGCAU

UCUCAGCG

UCAGCGCA

AGCGCAUG

AUAGAAGG

GAAGGAAC

AGACGGLU

1586 AAUGUGCU CUGAUGA X GAA ACCGUCUU AAGACGGUU AGCACAUU 162 1587 CAAUGUGC CUGAUGA X GAA AACCGUCU AGACGGUTUA GCACAUTUG 9 9 1594 1609 1611 1625 1627 1642 1643 1647 10 1652 1673 1678 1679 1680 15 1681 1685 1705 1706 1707 1712 1713 1714 1717 1756 1766 1770 1774 1775 1780 1790 1791 1799

CCACCAC

GGGUCUG

AGGGGUC

CAGCUGU

GGCAGCU

UULUUAUUi

AUUUUAU

CCCUAULJI

ACAGUCC(

UAAAAUUTI

UGACAUA2

GUGACAUI

UGUGACAt CUGUGAC7

ACAUCUGL

AAACGUGA

GAAACGUG

GGAAACGUJ

UCCAAGGA

UUCCAAGG

UUJUCCAAG

UCUUUUCC

CCACACAG

AAtJUUAUU

CAGGAAUU

UGUACAGG

CUGUACAG

UGUCUCUG

AUCCAGGU

AAUCCAGG

CGUAGCAG

'C CUGAUGA A CUGAUGA U CUGAUGA A CUGAUGA G CUGAUGA -0 CUGAUGA LJ CUGAUGA J3 CUGAUGA

CUGAUGA

J CUGAUGA k. CUGAUGA k CUGAUGA.

J CUGAUGA:

CUGAUGA

ICUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA)

CUGAUGA)

CUGAUGA 2 CUGAUGA Y~ CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X X GAA AUGUGCUA X GAA AGTJCAGCC X GAI\ AGAGUCAG K GAA AUUCCAGG K GAA AGAUTJCCA K GAA AGGCCCGG C GAA AAGGCCCG C GAA AUUGAAGG CGAA AUUUUAUU GAA AtJGUTJUCU 'GAA AUUUUAUG :GAA AAUUUTUAU GAA AAAUULTrJA GAA AAAAUUUUU GAA ACAUAAAA GAA AGCCAUTUC GAA AAGCCAUU GAA AAAGCCAU GAA ACGUGAAA GAA AACGUGAA GAA AAACGUGA GAA AGGAAACG GAA ACAGLJUUC GAA ACCACACA GAA AUUGACCA GAA AUUUAUUG GAA AAUUUALTI GAA ACAGGAAU GAA AUGUCUCU GAA AAUGUCUC GAA AUCCAGGU

UAGCACAU

GGCUGACU

CUGACUCUj(

CCUGGA.AU(

UGGAAUCUI

CCGGGCCLt

CGGGCCUUC

CCUUCAAU;z AAUAAAAU~z

AGAAACAUP.

CAUAAAAUUJ

AUAAAAUUU

UAAAAUUUUJ

AAAAUtUUJA

UUUTUAUGUC

GAAUGGCUU

AAUGGCUUU

AUGGCUUUC

UUtJCACGUU

UUCACGUUU

UCACGUUUTC

CGtJEUtCCUU

GAAACUGUC

UGUGUGGUC

UGGUCAAUA

CAAtJAAAUU

AAUAAAUTUC

ALUtCCUGUA

AGAGACAUJI

GAGACALUJA

ACCUGGALTU

U GGUGGUGG 2UCAGACCC

AGACCCCU

UACAGCUG

k. CAGCUGCC

JCAAUAAAA

AAtJAAAAU

AAAUAGGG

LGGGACUGU

6AAAUtJUUA

TJUAUGUCA

rUAUGUCAC

AUGUCACA

UGUCACAG

ACAGAUGU

UCACGUUU

CACGUUUC

ACGUUUCC

UCCUGGA

CCUUGGAA

CUUGGAAA

GGAAAAGA

CUGUGUGG

AAUAAALU

AAUUCCUG

CCUGUACA

CUGUACAG

CAGAGACA

ACCUGGAU

CCUGGALU

CUGCUACG

1800 CCGUAGCA CUGAUGA X GAA AAUCCAGG CCUGGAUUTC UGCUACGG 163 1805 ACUGUCCG CUGAUGA X GAA AGCAGAAU AUUCUGCUA CGGACAGU 1814 1815 1836 1839 1841 1866 1872 1873 10 1876 1880 1884 1892 1895 15 1898 1909 1911 1913 1921 1930 1952 1954 1970 1973 1974 1988 1989 1991 1994 1995 2001 2002 2021

CUGUTUGLI

UCUGUUTGI

GCUGAUAC

CUUGCUG]

UGCUUGCI

GUAAUCUL

GAUGGAGI.

UGAUGGAC

GAGUGAUC

UUCAGAGU

AAGGULJCP

UUGAUGAC

LUCLTUGAU

ACGUTUCUU

CUUCUAGA

GUCUUCUA

GAGUCUTUC

AGGUGCCC

UGCACGCA

CCUGUGUA

CCCCUGUG

UUCCGAAG

GUCUUCCG

UGUCUUCC

CUAACGAG

UCUAACGA

UCUCUAAC

GAAUCUCU

CGAAUCUC

CGCUUCCG

GCGCUUCC

AGGUUUUEG

J CUGAUGA J CUGAUGA

:CUGAUGA

k. CUGAUGA

JCUGAUGA

J CUGAUGA J CUGAUGA

;CUGAUGA

;CUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA2 CUGAUGA 3 CUGAUGA 2 CUGAUGA CUGAUGA I~ CUGAUGA Y~ CUGAUGA Y CUGAUGA X KGAA ACUGUCCG C GAA AACUGUCC C GAA AUGGUGCA C GAA ACUAUGGU I GAA AUACUAUG GAA AGUGGUGG GAA AUCUUJGAG GAA AAUCtJUGA GAA AGUAAUCU GAA AUGGAGUA GAA AGUGAUGG GAA AGGUUCAG GAA ACAAGGUU GAA AUGACAAG GAA ACACGUUC GAA AGACACGU GAA AGAGACAC GAA AGUCUUCU GAA AGGUGCCC GAA AUGUUCCU GAA AUAUGUUC GAA AUGUCUUC GAA AGGAUGUC GAA AAGGAUGU GAA ACUUCUGU GAA AACUUCUG GAA AGAACUUC GAA ACGAGAAC GAA AACGAGAA GAA AUCUCUAA GAA AAUCUCUA GAA AGCAGGUG

CGGACAGLTI

GGACAGUU;

UGCACCAU;z

ACCAUAGUJZ

CAUAGUAUC

CCACCACUC

CUCAAGAU

UCAAGAUUA

AGAUUACUC

UACUCCAUC

CCAUCACUC

CUGAACCUU

AACCUTUGUC

CUUGUCAUC

GAACGUGUC

ACGUGUCUC

GUGUCUCUA

AGAAGACUC

GGGCACCUA

AGGAACAUA

GAACAUAUA

GAAGACAUC

GACAUCCUU

ACAUCCLYTJC

ACAGAAGUIJ

CAGAAGUTUC

GAAGUUCUC

GUUCUCGtUU

UUCUCGUUA

UUAGAGAUU*

UAGAGAUUC

CACCUGCUU

JAACAACAG

SACAACAGA

LGUAUCAGC

LUCAGCAAG

AGCAAGCA

AAGAUUAC

ACUCCAUC

CUCCAUCA

CAUCACUC

ACUCUGAA

UGAACCUJ

GUCAUCAA

AUCAAGAA

AAGAACGU

UCUAGAAG

UAGAAGAC

GAAGACUC

GGGCACCU

UGCGUGCA

UACACAGG

CACAGGGG

CUJUCGGAA

CGGAAGAC

GGAAGACA

CUCGUtJAG

UCGUTUAGA

GUTUAGAGA

AGAGALUC

GAGAUUCG

CGGAAGCG

GGAAGCGC

CAAAACCU

2022 GAGGUUUU CUGAUGA X GAA AAGCAGGU ACCUGCUUC AAAACCUC .o 2030 2038 2045 2047 2051 2059 2061 2068 10 2069 2076 2082 2090 2100 2105 2109 2113 2114 2132 2150 2151 2153 2154 2155 2156 2179 2180 2181 2183 2192 2213 2215 2217

UAGUCAC

AGACCUC

CUGAUGG

CACUGAU

GAGCCAC'

AGGUCGII

UAAGGUC(

GACAGUCI

UGACAGU(

UCUAGCUI

GACACCUC

GGCGCGGC

AGUGAUat

AACCAAGL

UUUGAACC

UGUtUUUUG

LUJGULUJUU

UCUUGIJUG

CCUAAAAU

UCCUAAAA

GGUCCUAA

UGGUCCUA

CUGGUCCU

CCUGGUCC

UUtUCAAUA

CUUUCAAU

UCUUUCAA

ACUCULUJC

UCCUCUGU

CACCUAUA

GGCACCUA

UCGGCACC

U CUGAUGA G CUGAUGA A CUGAUGA G CUGAUGA UI CUGAUGA k. CUGAUGA 37 CUGAUGA J CUGAUGA

:CUGAUGA

J CUGAUGA

CUGAUGA

CUGAUGA

JCUGAUGA

FCUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA2 CUGAUGA2

CUGAUGA)

CUGAUGA 2 CUGAUGA Y~ CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X

GA

GA

GA

GA

GA

(GA

C GA C GA Gk

G,

GA;

GAI

GA7

GA;Z

GAP

GAP~

GAP,

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

AAGGUUUUG

AAGUCACUG

A ACCUCGUA A AGACCUCG

AAUGGAGAC

AAGCCACUG,

~AGAGCCAC

SAGGUCGUA

~AAGGUCGU-

~ACAGUCUA

~AGCUUGAC

~ACACCUCU

~AGGCGCGG

SAUCUGAGG

AGUGAUCU

ACCAAGUG

AACCAAGU

AUUUUTGUG

AUUCCCGG

AAUUCCCG

AUAAUTUCC

AAUAAUUC

AAAUAAUU

AAAAUAAU

ACAGCGUG

AACAGCGU

AAACAGCG

AUAAACAG

ACUCUTUUC

ACACCCUC

AGACACCC

AUAGACAC

CAAAACCU

CAGUGACLL

UACGAGGU

CGAGGUCU(

GUCUCCAUC

CAGUGGCU(

GUGGCUCUI

UACGACCUL

ACGACCUJp

UAGACUGUC

GUCAAGCUA

AGAGGUGUC

CCGCGCCUC

CCUCAGAUC

AGAUCACUU

CACUUGGUU

ACUUGGUUC

CACAAAAUA

CCGGGAALU

CGGGAAUUA

GGAAUTUALU

GAAUUAUUU

AAUUAJUTUtJ

AUUAUUUUA

CACGCUGUU

ACGCUGJUU

CGCUGUUETJA

CUGUUTUAUU

GAAAGAGUC

GAGGGUGUC

GGGUGUCUA

GUGUCUAUA

CAGUGACUA

N. CGAGGUCU

TJCCAUCAG

:CAUCAGUG

AGUGGCUC

UACGACCU

CGACCUtJA

AGACUGUC

LGACUGUCA

AAGCUAGA

GAGGUGUC

CCCGCGCC

AGAUCACU

ACUUGGUtJ

GGUUCAAA

CAAAAACA

AAAAACAA

CAACAAGA

AUtUJAGG

UUUUAGGA

UUtAGGACC

UAGGACCA

AGGACCAG

GGACCAGG

UAUUGAAA

AUUGAAAG

UUGAAAGA

GAAAGAGU

ACAGAGGA

UAUAGGUG

UAGGUGCC

GGUGCCGA

165

O)

2263 CGGTJGAGG CUGAUGA X GAI 0* .01.

*.00.

*so.

2267 2284 2293 2309 2315 2342 2344 2345 10 2346 2351 2354 2355 2357 2361 2363 2365 2366 2369 2386 2388 2389 2391 2392 2399 2410 2416 2420 2423 2424 2441 2442 2473 UGCACGGt

ACUUGUCL

CCAGGUUTI

GUGAGCGL

GUGCACGU

AGCCAA

GGAGCCAA

AGGAGCCA

AAGGAGCC

GUUAGAAG

AGAGUTUAG

GAGAGUUA

AAGAGAGU

GAUGAAGA

CUGAUGAA

UUCUGAUG

UUUCUGAU

AGUUUUCU

CGGAAGAA

UUCGGAAG

CUUJCGGAA

UACUUCGG

LTUACUUCG

UCUGUCUU

UUGACAGG

UAAUGALU

UCCAUAAU

GGGUCCAU

UGGGUCCA

UCCAGGGG

AUCCAGGG

UGGCAUCA

JCUGAUGA

JCUGAUGA

TCUGAUGA

ICUGAUGA

ICUGAUGA

*CUGAUGA

CUGAUGA

*CtJGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

C.UGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA;

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGAI

GA;

GA7

GA-T

GAl

GAP

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GMA

GMA

GAA

GMA

GMA

GAA

GAA

GMA

GMA

GMA

GMA

GMA

GMA

GMA

GMA

GMA

GMA

GMA

GMA

GMA

AGGCUGCG

SAGGUAGGC

AGGUUCCU

ACUUGUCU

AUCAGCUC

AGCGUGAU

AGGGUCGC

AGAGGGUC

MAGAGGGU

AAAGAGGG

AGCCAA

AGGAGCCA

MGGAGCC

AGMAGGAG

AGUUAGMA

AGAGUUAG

AGAGAGU

MAGAGAGU

AUGMAGAG

ACCGCUJC

AGACCGCU

MGACCGC

AGAAGACC

AGAAGAC

ACUTUCGGA

AGUCUGUC

ACAGGUAG

AUUGACAG

AUGALJUGA

AUGAJUG

ACUUCAUC

ACUJCAU

AGGGCAGC

CGCAGCCUj

GCCUACCU(

AGGAACCU(

AGAcMAGuC

GAGCUGAUC

AUCACGCUC

GCGACCCUC

GACCCUCU.

ACCCUCUUL

CCCUCUuUt UUtJUGGCUC

UGGCUCCUJL

GGCUCCUUC

CUCCUUCUA

UUCUAACUC

CUMACUCUC

MCUCUCUU

ACUCUCUTC

CUCUUCAUC

GMAGCGGUC

AGCGGUCUU

GCGGUCUUtC

GGUCUUCUU

GUCtUtCUUC

UCCGAAGUA

CACAGACUA

CUACCUGUC

CUGUCMAUC

UCAAUCALU

CMAUCAUUA

GAUGMAGUU

AUGAAGUUJC

GCUGCCCUA

~CCUCACCG

ACCGUGCA

AGACAAGU

SAAACCUGG

ACGCUCAC

ACGUGCAC

UUUJUGGCU

J UUGGCUCC

IUGGCUCCU

FGGCUCCUU

*CUUCUAAC

CIJAACUCU

UAACUCUC

*ACUCUCUU

UCUUICAUC

UUCAUCAG

CAUCAGAA

AUCAGAAA

AGAAAACU

UEJCULJCCG

CUTJCCGAA

UTUCCGAAG

CCGAAGUA

CGAAGUAA

AAGACAGA

CCUGUCAA

MAUCAUTUA

AUUAUGGA

AUGGACCC

UGGACCCA

CCd CUGGA

CCCUGGAU

UGAUGCCA

e 2494 CCCGUGCA CUGAUGA X GAA ACUCCCAC GtJGGGAGUU UGCACGGG 2495 2516 2524.

2528 2541 2542 2543 2552 10 2555 2556 2563 2569 2570 2576 2577 2584 2617 2644 2652 2666 2672 2674 2684 2691 2694 2705 2706 2711 2742 2753 2761 2770

UCCCGUG

GAUUUGC

UUCCGAGi CcUCUUCI UUUCCCAj

CUIJUCCO

ACUTUUCC(

GCUUGAAC

GAGGCIJUC

AGAGGCUT.

CAAAUGC;

UAAUGCC;

UUAAUGCC

GAUUUCUtJ UGAUUUCtJ

AGGUGGGU

CCUuUUC GAG CUEUG

GGUCAUCA

AAGAUCLU

UGGGUCAA

UGUGGGUC

UGAUGGCC

AUTUCAGAU

CACAUUCA

AGGAGGU

CAGGAGGU

GCUCCCAG

CACCAUCA

UAUTUCCAC

AUUUGCAG

GGUUUCCG

C CUGAUGA C CUGAUGA C CUGAUGA 2CUGAUGA k. CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

J CUGAIJGA

CUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I

CUGAUGAI

CTJGAUGA 2

CUGAUGA)

CUGAUGA CUGAUGA CUGAUGA Y CUGAUGA Y CUGAUGA Y CUGAUGA X X GAA AACUCCCA X GAA AGUUUCAG K GAA AUUUGCCU K GAA AGCGAUUU K GAA AGCCCCUC SGAA AAGCCCCU C GAA AAAGCCCC CGAA ACUUUCCC GAA ACGACUUU GAA AACGACUU GAA AGGCUUGA GAA AUG CAGAG GAA AAUGCAGA GAA AUGCCAAA GAA AAUGCCAA GAA AUUUCUUA GAA ACAUCUUC GAA ACUCACUG GAA AGCUUUGU GAA AGUUCGGU GAA AUCUUGAG GAA AGAUCUUG GAA AUGUGGGU GAA AUGGCCGA GAA AUGAUGGC GAA ACCACAUU1 GAA AACCACAU GAA AGGUUAAC GAA AGGCCCUC GAA AUCACCAU GAA AUUCCACG GAA AUUUGCAG

UGGGAGUU

CUGAAACU

AGGCAAAUi AAAUCGCUi GAGGGGCL71

AGGGGCULII

GGGGCUUUTI

GGGAAAGUC

AAAGUCGUL

AAGUCGUUC

UCAAGCCUC

CUCUGCAUL

UCUGCAUIJC

UTUUGGCAUTJ

UUGGCAUTUA

UAAGAAAUC

GAAGAUGUU

CAGUGAGUA

ACAAAGCUC

ACCGAACUC

CUCAAGAUC

CAAGAtJCUU

ACCCACAUC

UCGGCCAUC

GCCAUCAUC

AAUGUGGLU

AUGUGGUUA

GUUAACCUC

GAGGGCCUC

AUGGUGAUC

CGUGGAAUA

CUGCAAAUA

U GC-ACGGGA A~ GGCAAAUC C GCUCGGAA 2GGAAGAGG J UUGGGAAA J UGGGAAAG J GGGAAAGU

-GUUCAAGC

J CAAGCCuc

AAGCCUCU

UGCAUU7UG

TUGGCAUUJA

FGGCAUUAA

fAAGAAAUC

AGAAAUCA

ACCCACCU

GAAAGAGG

CAAAGCUC

UGAUGACC

AAGAUCUU

UUGACCCA

GACCCACA

GGCCAUCA

AUCUGAAU

UGAAUGUG

AACCUCCU

ACCUCCUG

CUGGGAGC

UGAUGGUG

GUGGAAUA

CUGCAAAU

CGGAAACC

167 2782 2788 2792 2809 2810 2812 2813 2817 2819 10 2836 2841 2849 2900 2909 15 2917 2924 2932 2938 2939 2982 2983 2993 2995 3008 3026 3027 3028 3031 3036 3037 3038 3061

GGUAGUUC

UCUUGAGC

UEJGCUCLL

GACAGAAI

AGACAGA;

UGAGACAC

UUGAGACP.

CUUtGLUGPA

UCCUUGUU

CCAUAUGC

GAGCUCCA

UCJUTJCUU

ACACUGUC

GAGCtJGCU

UGACACUU

GAG CUGGU

GGAAGCUG

CUUCAGGG

UCU.UCAGG

CUCACUGU

UCUCACUG

UGCUUGGA

GCUGCUUG

UCCAUGGU

CUGUAGGA

ACUGUAGG

AACUGUAG

GGAAACUG

CACUTUGGA

CCACUUGG

GCCACUULG

AGGACAGA

;CUGAUGA

CUGAUGA

J CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA 3

CUGAUGA)

CUGAUGA)

CUGAUGA)

GAP~

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAI

GAI

GA7

GA;

GAP

GA-P

\ACAGGUUU

AGUUJGGAC

AGGUAGUU

AGUCACGU

AAGUCACG

AUAAGUCA

AAUAAGUC

ACAGAAUA

*AGACAGAA

*AGGCUGCG

AUGCAAGG

AGCUCCAU

AGGCGGGG

ACACUGUC

AGCUGCUG

ACACUtJGA

AGCUGGUG

AGCUGGAG

AAGCUGGA

AUCCUCGU

AAUCCUCG

AUCUCACU

AGAUCUCA

AGGGGCtJG

AUCAGGUC

AAUCAGGU

AAAUCAGG

AGGAAAUC

ACUGUAGG

AACUGUAG

AAACUGUA

ACUCCAUG

AAACCUGU

GUCCAACU

AACtJACCU(

ACGUGACUI

CGUGACUUJ

UGACUUIAMt

GACUUAUUC

UAUUCUGUC

UEJCUGUCUC

CGCAGCCtJC

CCUUGCAUP

AUGGAGCUC

CCCCGCCUA

GACAGUGUC

CAGCAGCUC

UCAAGUGUC

CACCAGCUC

CUCCAGCUU

UCCAGCLTUC

ACGAGGAUU

CGAGGAUUJA

AGUGAGAUC

UGAGAUCUC

CAGCCCCUC

GACCUGAUEJ

ACCUGAUUUJ

CCUGALTUUC

GAUUUCCUA

CCUACAGUU

CUACAGUUU

UACAGUUUC

CAUGGAGUU

:7 CAACUACC k. CCUCAAGA

AAGAGCAA

J AUUCUGUC kUUJCUGUCU

JCUGUCUCA

UGUCUCAA

UCAACAAG

AACAAGGA

GCAUAUGG

UGGAGCUC

AAGALAAGA

GACAGUGU

'AGCAGCUC

AAGUGUCA

ACCAGCUC

CAGCUUCC

CCCUGAAG

CCUGAAGA

ACAGUGAG

CAGUGAGA

UCCAAGCA

CAAGCAGC

ACCAUGGA

UCCUACAG

CCUACAGU

CUACAGUU

CAGUUUCC

UCCAAGUG

CCAAGUGG

CAAGUGGC

UCUGUCCU

3062 GAGGACAG CUGAUGA X GAA AACUCCAU AUGGAGUUU CUGUCCUC 168 3063 GGAGGACA CUGAUGA X GAA AAACUCCA o 0 3067 3070 3083 3084 3087 3110 3113 3114 10 3115 3116 3118 3140 3141 15 3148 3149 3165 3167 3168 20 3169 3171 3183 3184 3201 3204 3209 3210 3215 3228 3235 3239 3241 3242

UUCUGGA

ACLUUCU,

UCCCGAU

GUCCCGAI

CAGGUCC(

GAUAAAA(

UCAGAUA)

CUCAGAUZ

UCUCAGAt.

UUCUCAGI

UGUUCUU.

AAGUCGCP

AAAGUCGC

CCAGGCCA

GCCAGGCC

CUUAUAAA

LUCUUAUA

GUtJCUUAU

GGUUCUTUA

AGGGTJUCU

CCUCACAU

UCCUCACA

AAGUCGAG

GGGAAGUC

UUtJAGGGG UUtJUAGGG

AUCCAUU

GGALTUCAG

CAAAGAUG

UUGUCAAA

CCUUGUCA

ACCUGUC

G CUGAUGA 3 CUGAUGA 3 CUGAUGA J3 CUGAUGA

CUGAUGA

SCUGAUGA

k~ CUGAUGA

~CUGAUGA

J CUGAUGA

SCUGAUGA

CUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA)

CUGAUGA

CUGAUGA 2 CUGAUGA Y~ CUGAtJGA Y~

GA)

GAJ

GA)

GA7 GM7

GAP

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

ACAGAAAC

'AGGACAGA

~AUGCACU

~AAUGCACU

SAUGAAUGC

AUGUUUCU

AGGAUGUU

AAGGAUGU

AAAGGAUG

AAAAGGAU

AUAAAAGG

AUCIJUCAC

AAUCUTUCA

AGUCGCAA

AAGUCGCA

AUCCCGGG

AUAUCCCG

AAUAUCCC

AAAUAUCC

AUAAAUAU

AUCAGGGU

AAUCAGGG

AUCUCCUC

AGUAUCUC

AGUCGAGU

AAGUCGAG

AGGGGAAG

AGCCAUCC

AUtJCAGGA

AUGGAUJC

AGAUGGAU

AAGAUGGA

UGGAGUUUC

UGUCCJCC

GULUCIJGUC

CUCCAGAA

UCUGUCCUC

CAGAAAGU

AAGUGCAULJ CAUCGGGA AGUGCAUUC

AUCGGGAC

GCAUUCAUC

GGGACCUG

AGAAACAUC

CUUTUUAUC

AACAUCCUU

UUAUCUGA

ACAUCCUTUU

UAUCUGAG

CAUCCUUUU

AUCUGAGA

AUCCUUUUA

UCUGAGAA

CCUUUUAUC UGAGAACA GUGAAGAUU UGCGACUU UGAAGAUtJI GCGACUUU UUGCGACUU UGGCCUGG UGCGACUUU

GGCCLJGGC

CCCGGGAUA UUUAUAAG CGGGAUAUUT UAUAAGAA GGGAUAUU AUAAGAAC GGAIJAUUUA

UAAGAACC

AUAUUUAUA

AGAACCCU

ACCCUGAUU

AUGUGAGG

CCCUGAUJA

UGUGAGGA

GAGGAGAUA

CUCGACUU

GAGAtJACUC

GACULJCCC

ACUCGACUU CCCCUAAA CUCGACUUC

CCCUAAAA.

CUUCCCCUA AAAUGGAU GGAUGGCUC CUGAAUCC UCCUGAAUC

CAUCUUTUG

GAAUCCAUC

UUUGACAA

AUCCAUCUU

UGACAAGG

UCCAUCUUtJ GACAAGGU 169 3251 GUGCUGUA CUGAUGA X GAA ACCUUGUC GACAAGGUC UACAGCAC C

S

*5 S S *54 *5*S

S

*5*5 *5*S S S. C

S

3253 3277 3280 3289 3302 3304 3305 3307 10 3310 3311 3318 3319 3321 15 3325 3352 3353 3397 341.3 3415 3422 3427 3432 3466 3467 3476 3488 3500 3501 3512 3531 3532

UGGUGCU(

CGCCAUAC

ACACGCC)

CC CACAG C

AAGGAGAZ

CUAAGGAC

CCUAAGGP

CCC CUAAC

AACCCCCJ

GAACCCCC

GUAUGGAG

GGUAUGGA

UGGGUAUG

CUCCUGGG

GGCUGCAG

CGGCUGCA

GUGUGGCA

AUUUGGUA

UGAUUUGG

UCCAACAU

AGCAAUCC

GUGCCAGC

GUUCAGCA

AGLUJCAGC

UUCUCCAC

AGGUCACC

UTUGGCUUG

GUUGGCUU

UCCUGLTUG

GGGGAUGU

GGGGGAUG

3CUGAUGA 3 CUGAUGA k CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2 CUGAUGA2 CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA 2 CUGAUGA I~ CUGAUGA Y~ C GAA AGACCUUG GAA ACCACACA C GAA AGGACCAC I GA.A ACACGCCA GAA AUCUCCCA GAA AGAUCUCC GAA AAGAUCUC GAA AGAAGAUC GAA AGGAGAAG GAA AAGGAGAA GAA ACCCCCUA GAA AACCCCCU GAA AGAACCCC GAA AUGGAGAA GAA AGUCUUCA GAA AAGUCUtJC GAA ACUCCGGG GAA AUIJUCAGG GAA AGAUUUCA GAA AUUJUGGUA GAA ACAUGAUUJ GAA AUCCAACA GAA ACCGGGGC GAA AACCGGGG GAA AGUUCAGC GAA AGUUUCUC GAA AGCAGGUC GAA AAGCAGGU GAA ACGUUJGGC GAA AUCUUUCC GAA AAUCUUUC

CAAGGUCUI

UGUGUGGUC

GUGGUCCU;

UGGCGUGUL

UGGGAGAUC

GGAGAUCUU

GAGAUCUUC

GAUCLUUC

CUUCUCCUU

UUCUCCUUA

UAGGGGGUU

AGGGGGUUC

GGGGUUCUC

UUCUCCAUA

UGAAGACUU

GAAGACUUC

CCCGGAGUA

CCUGAAAUC

UGAAAUCUA

UACCAAAJC

AAUCAUGLU

UGUTUGGAUU

GCCCCGGUU

CCCCGGUUU

GCUGAACUU

GAGAAACUU

GACCUGCUU

ACCUGCUUC

GCCAACGUC

GGAAAGAUU

GAAAGAUUA

CAGCACCA

CUAUGGCG

UGGCGUGU

GCUGUGGG

UTUCUCCUU

CUCCUUAG

UCCtTUAGG

CUUAGGGG

AGGGGGUU

GGGGGUUC

CUCCAUAC

UCCAUACC

CAUACCCA

CCCAGGAG

CUGCAGCC

UGCAGCCG

UGCCACAC

UACCAAAU

CCAAAUCA

AUGUUGGA

GGAUTUGCU

GCUGGCAC

UGCUGAAC

GCUGAACU

GUGGAGAA

GGUGACCU

CAAGCCAA

AAGCCAAC

CAACAGGA

ACAUCCCC

CAUCCCCC

3536 UUGAGGGG CUGAUGA X GAA AUGUAAUC GAUUACAUC CCCCUCAA 170 3542 AUGGCAUU CUGAUGA X GAA AGGGGGAU AUCCCCCUC AAUGCCAU

S

*5

S

I S

S.

5 5

S

S..

ease too.

3551 3558 3567 3571 3572 3577 3580 3592 10 3593 3595 3605 3606 3607 3608 3619 3620 3627 363 3634 3635 3636 3639 3640 3649 3664 3668 3675 3676 3677 3682 3683 3701

CUAGUCP

ACUGUUL

UGUGAAG

AGUAUGU

GAGUAUG

GGGUCGA

UGGGGGU

CCUCAGA

UCCUCAG,

GGUCCUC

UCCUUGAj

GUCCUUG)

CGUCCUJC

CCGUCCUL

GAUCUGC;

GGAUCUGC

AAAAUGUC

GGAAUGAA

CGGAAUGA

CCGGAAUG

UCCGGAAU

GCUUCCGG

AGCUUCCG

CAUCAUCA

CGLUUtACA

AAAGCGU

GAAUUTUGA

UGAAUUUG

AUGAAUUU

GGCUCAUG

AGGCtJCAU

AAGGUUUU

LG CUGAUGA IC CUGAUGA C CUGAUGA G CUGAUGA U CUGAUGA G CUGAUGA C CUGAUGA -0 CUGAUGA k CUGAUGA k. CUGAUGA

CUGAUGA

k CUGAUGA

;CUGAUGA

JCUGAUGA

CUGAUGA

CUGAUGA

CUGATJGA

*CUGAUGA

*CUGAUGA 3 CUGAUGA CUGAUGA CUGAUGA

Y~

CUGAUGA

Y

CUGAUGA

Y

CUGAUGA

X

CUGAUGA

X

CUGAUGA

X

CUGAUGA X CUGAUGA

X

CUGAUGA

X

CUGAUGA

X

CUGAUGA X X GAA AUGGCAUUJ X GAA AGUCAGUA X GAA ACUGUUUC X GAA AGCUACUG X GAA AAGCUACU X GAA AUGUGAAG X GAA AGUAUGUG X GAA AGGUGGGG X GAA AAGGUGGG X GAA AGAAGGUG X GAA AGGUCCUC X GAA AAGGUCCU X~ GAA AAAGGUCC KC GAA AAAAGGUC K GAA AGCCGUCC K GAA AAGCCGUC C GAA AUCUGCAA C GAA AUGUGGAU C GAA AAUGUGGA GAA AAAUGUGG GAA AAAAUGUG GAA AUGAAAAU 1GAA AAUGAAAA GAA AGCUUCCG GAA AUCUCACA GAA ACAUAUCU GAA AGCGUUUA GAA AAGCGLUU GAA AAAGCGUU GAA AUUUGAAA GAA AAUUUGAA GAA AUUCUUUC

AAUGCCAU

UACUGACU

GAAACAGU,

CAGUAGCU

AGUAGCUUC

CUUCACAU)

CACAUACU(

CCCCACCUL

CCCACCUUC

CACCUUCUC

GAGGACCL

AGGACCUUU

GGACCLTUUU

GACCUUEJUC

GGACGGCuU

GACGGCUUUJ

tJUGCAGAUC

AUCCACAUU

UCCACAUUU

CCACAUUUU

CACAUUUUC

AUUUUtCAUU

UUUUCAUUC

CGGAAGCUC

UGUGAGAUA

AGAUAUGUA

UAAACGCUUI

AAACGCUtU

AACGCUUUC

UUUCAAAUU

UUCAAAUuC

GAAAGAAUC

A CUGACUAG A. GAAACAGU k. GCtJUCACA J CACAUACU ACAtJACUC k CUCGACCC

SGACCCCCA

CUCtJGAGG

UCUGAGGA

UGAGGACC

FUUCAAGGA

IUCAAGGAC

CAAGGACG

AAGGACGG

tJGCAGAUC

GCAGAUCC

CACAUUUU

UUCAUUCC

UCAUTUCCG

CAUtJCCGG

AUTUCCGGA

CCGGAAGC

CGGAAGCU

UGAUGAUG

UGUAAACG

AACGCUUtJ

UCAAAUUC

CAAAUUCA

AAAUTUCAU

CAUGAGCC

AUGAGCCU

AAAACCUU

3709 GCUCCUCA CTJGAUGA X GA.

3710 3719 3720 3721 3730 3736 3742 3743 3751 3753 3765 3771 3781 15 3787 3799 3800 3829 3839 3844 3851 3858 3878 3879 3880 3885 3901 3902 3907 3908 3910 3926 3949

AGCUCCU

UUtCGGUG,

GUUCGGU

AGUTUCGGI

UGGAGGtJ(

CAAACAUC

AGUCCUCJ

UAGUCCUC

CCAGCUG]

GUCCAGCI

CAGAGUGC

GCCCAGU.

GCAAGGGC

GCUUCAGC

UCCAGGUG

GUCCAGGUJ

UCUTUCAUG

CUCAAGUC

CUAUTUCUC

UUACUCGC

CUUGCUUU

AGAUCGGA

CAGAUCGG

GCAGAUCG

CCUCGGCA

AGAAGCAG

GAGAAGCA

AGCUGGAG

CAGCUGGA

CACAGCUG

ACGGGCCU

CCAGCUCA

C CUGAUGA Ik CUGAUGA 3 CUGAUGA J CUGAUGA 3CUGAUGA 3CUGAUGA k CUGAUGA

CUGAUGA

CUGAUGA

J CUGAUGA 7CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA)

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA Y CUGAUGA Y CUGAUGA y K G& K GA K G K GA C GA2 C GIA CGA7 rGAM

GAP

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

~AGGULTUUG

~AAGGLTUUU

~AGCUCCUC

~AAGCUCCU

~AAAGCUCC

~AGUUCGGU

~AGGUGGAG

SACAUGGAG

AACAUGGA

AGUCCUCA

AUAGUCCU

AGUGUCCA

AGUGCUAG

AGCCCAGC

AGGGGGAG

AC CCCUUC

AACCGCUU

AGGCCUUG

AUCUTUCAU

AGUCUAUC

AtJUCUCAA

ACUCGCUA

AGUCCCGC

AAGUCCCG

AAAGUCCC

AUCGGAAA

AGCUGGGC

AAGCUGGG

AGCAGAAG

AAGCAGAA

AGAAGCAG

AUGUGGCC

AUUCAUCG

CAAAACCU

AAAACCUU1

GAGGAGCU

AGGAGCUUI

GGAGCUtJU(

ACCGAACUC

CUCCACCU(

CUCCAUGU.

UCCAUGUUI.

UGAGGACU;

AGGACUAUC

UGGACACUP

CUAGCACUC

GCUGGGCUC

CUCCCCCUU

GAAGCGGUU

AAGCGGUUC

CAAGGCCUC

AUGAAGAUA

GAUAGACU

UUGAGAAUA

UAGCGAGUA

GCGGGACUtJ

CGGGACUUU

GGGACULTJUC

UTUUCCGAUC

GCCCAGCUtj

CCCAGCUUC

CUTUCUGCUEJ

UTUCUGCUJC

CUGCUUCUC

GGCCACAUC

CGAUGAAUC

UJ UGAGGAGC LT GAGGAGCU J3 UCACCGAA J CACCGAAC

ACCGAACU

:CACCUCCA

:CAUGUUUG

J UGAGGACU

IGAGGACUA

UCAGCUGG

AGCUGGAC

GCACUCUG

UGCUGGGC

CCCCUtJGC

GCUGAAGC

CACCUGGA

ACCUGGAC

CAUGAAGA

GACUUJGAG

GAGAAUAG

GCGAGUAA

AAAGCAAG

UCCGAUCU

CCGAUCUG

CGAUCUGC

UGCCGAGG

CUGCUTUCU

UGCUUCUC

CUCCAGCU

UCCAGCUG

CAGCUGUG

AGGCCCGU

UGAGCUGG

172 3967 AACAGCAG CUGAUGA X GAA ACUCCULJ AAAGGAGUC CUGCIJGUU 3975 3976 3978 3991 3997 4006 4009 4012 4015 4027 4033 4034 4036 4066 4068 4069 4071 4075 4077 4083 4084 4085 4091 4093 4094 4099 4117 4118 4119 4120 4128

GGGUGGA

GGGGUGG

UGGGGGU,

CGGAGU

ACACCAC(

AGGAGUA(

GGGAGGA(

GCGGGGA(

CGGGCGGC

AGAAGCUI

CUGGUGAC

GCUGGUG;

GGGCUGGL

AUGUAUAP

AGAUGUAtJ

UAGAUGUA

CAUAGAUG

AACUCAUA

UAAACUCA

UAGGUGUA

AUAGGUGU

AAUAGGUG

GAGCGGAA

UGGAGCGG

GUGGAGCG

CUCCUGUG

GUCACGAA

GGUCACGA

AGGUTCACG

AAGGUCAC

CACGAUUA

G CUGAUGA A~ CUGAUGA Sy CUGAUGA 3 CUGAUGA 3CUGAUGA

CUGAUGA

3CUGAUGA

SCUGAUGA

CUGAUGA

JCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

LCUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA)

CUGAUGA

CUGAUGA 2 CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X X GAA ACAGCAGG X GAA AACAGCAG X GAA AGAACAGC X GAA AGUCUGGG X GAA AGUUGUAG X GAA ACACCACG X GAA ACAACACC X GAA AGUACAAC X GAA AGGAGUAC X GAA AGGCGGGC X GAA AGCUUtJAG X GAA AAGCUUUA X GAA AGAAGCUU X GAA ACUGUCAG X GAA AUACUGUC K GAA AAUACUGU K GAA AUAAUACU SGAA AUGUAUAA SGAA AGAUGUAU C GAA ACUCAUAG C GAA AACUCAUA IGAA AAACUCAU GAA AGGUGUAA GAA AUAGGUGU GAA AAUAGGUG GAA AGCGGAAU GAA AGCAGCUG GAA AAGCAGCU GAA AAAGCAGC GAA AAAAGCAG GAA AGGUCACG

CCUGCUGU

CUGCUGUU

GCUGLTUCU

CCCAGACU

CUACAACU

CGUGGUGU

GGUGUUGU)

GUUGUACUC

GUACUCCU(

GCCCGCCUI

CUAAAG CUt

UAAAGCUUC

AAGCUUTCUC

CUGACAGUP

GACAGUAUU

ACAGUAUTUA

AGUAUUAUA

UUAUACAUC

AUACAUCUA

CUAUGAGUU

UAUGAGUULJ

AUGAGUUUA

UUACACCUA

ACACCUAUU

CACCUAUUC

AUUCCGCUC

CAGCUGCUU

AGCUGCUUU

GCUGCUUUJ

CUGCLTUUUC

CGUGACCUU

U CUCCACCC C UCCACCCC C CACCCCCA 6AACUCCG

:CGUGGUGU

J GUACUCCU k CUCCUCCC

CUCCCCGC

SCCCGCCCG

kAAGCUUTCU

JCUCACCAG

UCACCAGC

ACCAGCCC

LULWAUACAU

IAUACAUCU

UACAUCUA

CAUCUAUG

UAUGAGUU

UGAGUUUA

UACACCUA

ACACCUAU

CACCUAUU

UUCCGCUC

CCGCUCCA

CGCUCCAC

CACAGGAG

LUUCGtJGAC

UCGUGACC

CGUGACCU

GUGACCUU

UAAUCGUG

4129 GCACGAUU CUGAUGA X GAA AAGGUCAC GUGACCUUU AAUCGUGC 173 a a.

a a. a a 4130 4133 4139 4140 4141 4142 4143 4146 4147 4148 4149 4150 4153 4154 1 4155 4158 4159 4162 4165 4171 4172 4173 4178 4189 4198 4199 4216 4219 4221 4224 4225 4233 4249

AGCACGAI

AAAAGCA(

AAACAAAj AAAACAA2 AAAAACA2

AAAAAACJ

CAAAAAAC

AAACAAA;Z

AAAACAA7

CAAAACA-Z

ACAAAACT

AACAAAAC

ACAAACAA

AACAAACA

CAACAAAC

CAACAACA

GCAACAAC

ACAGCAAC

AAAACAGC

UUAGUCAA

GUUAGUCA

UGUUAGUC

AUIJCUUGU

ACUGGGGTJ

ACGUCACU

CACGUCAC

AACAAUAG

UCUAACAA

UCUCUAAC

GAUTLTCUC

GCGGGGGG

GUEJACCCTJ

JI CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

k~ CUGAUGA k. CUGAUGA

CUGAUGA

SCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA i CUGAUGA2 CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA 2 CUGAUGA Y~ CUGAUGA Y~ CUGAUGA Y K GAA AAAGGUCA CGAA AUUAAAGG C GAA AGCACGAU C GAA AAGCACGA C GAA AAAGCACG GAA AAAAGCAC GAA AAAAAGCA GAA ACAAAAAA GAA AACAAAAA GAA AAACAAAA GAA AAAACAAA GAA AAAAACAA GAA ACAAAAAA GAA AACAAAAA.

GAA AAACAAAA GAA ACAAAACA GAA AACAAAAC GAA ACAAACAA GAA ACAACAAA GAA ACAGCAAC GAA AACAGCAA GAA AAACAGCA GAA AGUCAAAA GAA ACAUUCUU GAA ACUGGGGU GAA AACUGGGG GAA AUUCUUCA GAA AGUAUUCU GAA AUAGUAUUl GAA ACAAUAGU GAA AACAAUAG GAA AUUTUCUCU GAA AGGCUIJUG UGACCUU2

CCUUUAAU(

AUCGUGCLTI

UCGUGCUUJI

CGUGCUUU.

GUGCUUUUL

UGCULTJUUL

UUUUtUUGU'L

UUUUUGUUL

UULJGUUtJI

UUUGUUUUU

UTUGUUUUUU

UUUUJUUGUU

UtUUTJUGUUJ tJUUUGULUU

UGUUTUUGUU

GUUtJUGUIU

UUGUUUGUU

tJUUGIJUGUU

GUUGCUGUU

UUGCUGUJU

UGCUGUUUEJ

UtJUUGACUA

AAGAAUGUA

ACCCCAGUU

CCCCAGUUJA

UGAAGAAUA

AGAAUACUA

AAUACUAJU

ACUAUUGUU

CUAUUGULJA

AGAGAAAUC

CAAAGCCUC

~AUCGUGCU

GUGCUUUU

J UUUTUGULU J JUGTUUU

JUUGUUJUU

J UGUUUUU JGUtUtUULUG

TUUUUGUUU

rULUUGUUIJUU r UUGUUTUUG

IUGUUUUGU

GUUUUGUUI

UUGUUUGU

UGUJUUGUU

GUUUGUU.G

UGUUGUUG

GUJUGUTJGC

GUUGCUGU

GCUGUUUU

UUGACUAA

UGACUAAC

GACUAACA

ACAAGAAU

ACCCCAGU

AGUGACGU

GUGACGUG

CUAUUGUU

UUGUUIAGA

GUtJAGAGA

AGAGAAAU

GAGAAAUC

CCCCCCGC

AGGGUAAC

a a a..

4255 4282 432i 4341 4350 4358 4359 4363 4387 4391 4393 4395 4397 4398 4445 4446 4456 4460 4487 20 4492 4500 4501 4509 4510 4512 4516 4524 4531 4532 4533 4543 4544

GUCCAGG'

GGUCGCC

GCUGCAG(

ACUGCCU(

AAUGGGCI

CAUGAGCI

CCAUGAGC

GCAGCCAI

GAGAGACI

AUAAGAG;

CCAUAAG.P

CUCCAUAP

UCCUCCAU

UIJCCUCCA

GCAUCCCA

CGCAUCCC

ACAGGACG

CUCCACAG

GCAUAGCG

AAGUGGCA

AGUCACUG

AAGUCACU

GGAGUGAG

AGGAGUGA

CCAGGAGU

GAGGCCAG

AAACAGCG

GGGCCCGA

GGGGCCCG

'GGGGGCCC

CCUCUTUGG

ACCUCUUG

U CUGAUGA P, CUGAUGA

SCUGAUGA

CUGAUGA

J CUGAUGA J CUGAUGA

-CUGAUGA

J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:I

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA)

CUGAUGA)

CUGAUGA 2 CUGAUGA Y CUGAUGA Y~ CUGAUGA Y CUGAUGA X KC GAA ACCCUGAG K' GAA AGGCACCU -K GAA AGGGUGGG ~GAA AGUCCCAC C GAA ACUGCCUC C GAA AUGGGCUU C GAA AAUGGGCU CGAA AGCUAAUG GAA AGCAGGUC GAA ACAGAGCA GAA AGACAGAG GAA AGAGACAG GAA AGAGAGAC GAA AAGAGAGA GAA AGCCUUU GAA AAGCCUUUT GAA ACGCAUCC GAA ACGGACGC GAA AGCCCCCU GAA AGCGGAGC GAA AGUGGCAU GAA AAGUGGCA GAA AGUCACUG GAA AAGUCACU GAA AGAAGUCA GAA AGUGAGAA GAA AGGCCAGG GAA ACAGCGGA GAA AACAGCGG GAA AAACAGCG GAA AGGGGGCC GAA AAGGGGGC

CUCAGGGU

AGGUGCCU(

CCCACCCU(

GUGGGACU)

GAGGCAGLZ

AAGCCCAUTL

AGCCCAUU;

CAUUAGCUC

GACCUGCUC

UGCUCUGUC

CUCUGTJCUC

CUGUCUCUC

GUCUCUCUUI

UCUCUCUTUA

AAA.AGGCUU

AAAGGCUUU

GGAUGCGUC

GCGUCCGUC

AGGGGGCUC

GCUCCGCUA

AUGCCACUU

UGCCACUUC

CAGUGACUU

AGUGACUUC

UGACUUCUC

UUCUCACUC

CCUGGCCUC

UCCGCUGtU

CCGCUGUUU

CGCUGUJEUC

GGCCCCCUU

GCCCCCUUC

~ACCUGGAC

UGGCGACC

CCTJGCAGC

kGAGGCAGU k AGCCCAUU

JAGCUCAUG

GCUCAUGG

AUGGCUGC

UGUCUCUC

UCUCUTUAU

UCUUJAUGG

UJUAUGGAG

AUGGAGGA

UGGAGGAA

UGGGAUG.C

GGGAUGCG

CGUCCUGU

CUGUGGAG

CGCUAUGC

UGCCACUU

CAGUGACU

AGUGACU

CUCACUCC

UCACUCCU

ACUCCUGG

CUGGCCUC

CGCUGUUUT

UCGGGCCC

CGGGCCCC

GGGCC CCC

CCAAGAGG

CAAGAGGU

4553 UGCUCUGA CUGAUGA X GAA ACCUCUUG CAAGAGGUA UCAGAGCA 175 9* 9* .9 9 9 4555 4577 4578 4579 4582 4598 4599 4602 4614 4615 4618 4620 4621 4625 4627 4628 4629 4630 4639 4641 4642 4646 4649 4653 4654 4655 4660 4669 4671 4672 4673 4682 4698

UCUGCUCI

GUCUAGGI

GGUCUAGC

UGGUCUAC

CCCUGGUC

UUCCCGAC

GUUCCCG;

UGGUUCCC

UUAAGAUL

LUUAAGAIJ

AGAUUTUAA

AAAGAUUU

AAAAGAtU

CGGGAAAA

CCCGGGAA

UCCCGGGA

CUCCCGGG

ACUCCCGG

CAACAGAA

GACAACAG

AGACAACA

AAACAGAC

GGUAAACA

GGAUGGUA

UGGAUGGU

UUGGAUGG

AUGCLTG

AUGUTUAAA

ACAUGUUA

CACAUGUU

ACACAUGU

CCCCCACU

CAGAAG CC J CUGAUGA k~ CUGAUGA 3CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

FCUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2 CUGAUGA2

CUGAUGA

CUGAUGA

C GAA AUACCUCU C GAA ACGUCCCU GAA AACGUCCC GAA AAACGUCC GAA AGGAAACG GAA ACAUGUGC GAA AACAUGUG GAA AGAACAUG GAA ACUGUGGU GAA AACUGUGG GAA AUUAACUG GAA AGAUUAAC GAA AAGAUUAA GAA AUUUAAGA GAA AGAUTUUAA GAA AAGAUUUA GAA AAAGAUUU GAA AAAAGAUU GAA ACUCCCGG GAA AGACUCCC GAA AAGACUCC GAA ACAGAAGA GAA ACAACAGA GAA ACAGACAA GAA AACAGACA GAA AAACAGAC GAA AUGGUAAA GAA AUG CUUUG GAA AUAUGCUU GAA AAUAUGCU GAA AAAUAUGC GAA ACACAUGU GAA AGCGCCAC

AGAGGUAU(

AGGGACGUL

GGGACGUUI

GGACGUUJC

CGUUtUCCU7

GCACAUGUL

CACAUGUUC

CAUGUUCUC

ACCACAGUU

CCACAGUUA

CAGUUAAUC

GUUAAUCUU

UUAAUCUUA

UCUUAAAUC

UUAAAUCUU

UAAAUCUUU

AAAUCUUUU

AAUCUUUUC

CCGGGAGUC

GGGAGUCUU

GGAGUCUUC

UCUUCUGUU

UCUGUUGUC

UUGUCUGUU

UGUCUGUUU

GUCUGUUUA

ULUACCAUC

CAAAGCAUA

AAGCAUAUU

AGCAUAUUU

GCAUAIJEJUA

ACAUGUGUC

GUGGCGCUtJ

-AGAGCAGA

J UCCUAGAC J CCUAGACC

CUAGACCA

GACCAGGG

I CUCGGGAA

UCGGGAAC

GGGAACCA

AAUCUUAA,

'AUCUUAAA

UUAAAUCU

AAAUCUUU

AAUCUUUU

UUUUCCCG

U!JCCCGGG

UCCCGGGA

CCCGGGAG

CCGGGAGU

UUCUGUUG

CUGUUGUC

UGUUGUCU

GUCUGUUU

UGUUUACC

UACCAUCC

ACCAUCCA

CCAUCCAA

CAAAGCAU

UTJUAACAU

UAACAUGU

AACAUGUG

ACAUGUGU

AGUGGGGG

GGCLTECUG

176 4703 GGCCUCAG CUGAUGA X GA) a 4704 4720 4723 4727 4728 4731 4733 4745 4751 4754 4763 4777 4778 4783 .478 9 4799 4800 4807 4812 4813 4819 4822 4827 4832 4843 4855 4856 4857 4858 4866 4867 4868

UGGCCUCJ

GAACUGAT

GAGGAACT

ACUAGAG(

CACUAGAC

UCUCACUW

CAUCUCAC

AUGACCUC

UUGGGUALj

AGCUUGGG

AGGCCUGC

AGUAUGCG

CAGUAUGC

GUGAGCAG

CUCCCCGU

GACCACUU

GGACCACU

CCAAACUG

CUAGGCCA

ACUAGGC C

AACCLUUAC

GGCAACCU

CAGUAGGC

CCCAUCAG

UGGCULUU

CUGULUAA

CCUGUUUA

ACCUGUUU

AACCUGUU

UGAGAUAA

UUGAGAUA

CUUGAGAU

k. CUGAUGA J CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA 2

CUGAUGA

CUGAUGA Y CUGAUGA Y X GA) K GA; K GA7 .K GA7

GAP

CGAP

C GA1A IGA7A

G-AA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GA).

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

~AGCCAAGC

~AAGCCAAG

~AUGGCUCU

SAUGAUGGC

SACUGAUGA

AACUGAUG

AGGAACUG

AGAGGAAC

AUGCAUCU

ACCUCAAU

AUGACCUC

AGCUUGGG

AGGUCAGG

AAGGUCAG

AUG CGAAG

AGCAGUAU

ACUCCCCG

AACUCCCC

ACCACUULA

ACUGGACC

AACUGGAC

AGGCCAAA

ACUAGGCC

ACCUUACU

AGGCAACC

AGCCCAUC

AUGUGGCU

AAUGUGGC

AAAUGUGG

AAAAUGUG

ACCUGUUU

AACCUGUU

AAACCUGU

GCUUGGCUI

CUUGGCUU(

AGAGCCAUC

GCCAUCAUC

UCAUCAGUI

CAUCAGtJUC

CAGUUCCUC

GUUCCUCP

AGAUGCAUUL

AUUGAGGUC

GAGGUCAUA

CCCAAGCUU

CCUGACCUU

CUGACCUUC

CUUCGCAUA

AUACUGCUC

CGGGGAGUU

GGGGAGUUA

UAAGUGGUC

GGUCCAGUU

GUCCAGUUJ

UUUGGCCUA

GGCCUAGUA

AGUAAGGUU

GGUUGCCUA

GAUGGGCUC

AGCCACAUU

GCCACAUUU

CCACAUUUJ

CACAUUUUTA

AAACAGGUU

AACAGGUUU

ACAGGUUUU

J CUGAGGCC

UGAGGCCA

AUCAGUUC

SAGUUCCUC

JCCUCUAGU

CUCUAGUG

UAGUGAGA

LGUGAGAUG

IGAGGUCAU

AUACCCAA

CCCAAGCU

GCAGGCCU

CGCAUACU

GCAUACUG

CUGCtJCAC

ACGGGGAG

AAGUGGUC

AGUGGUCC

CAGUUUGG

UGGCCUAG

GGCCUAGU

GUAAGGUJ

AGGUUGCC

GCCUACUG

CUGAUGGG

AAAAGCCA

UUAAACAG

UAAACAGG

AAACAGGU

AACAGGUU

UTLJAUCUCA

UAUCUCAA

AUCUCAAG

177

C

C

4869 4871 4873 4878 4880 4881 4884 4886 4888 4900 4901 4907 4908 4910 4915 4916 4917 4918 4920 20 4922 4924 4933 4935 4948 4949 4955 4961 4963 4974 4975 4976 4978 4982

ACUTUGAG,

AUACUUG

UAAUACU1 UAUALUUA2

UAUAUAUI

CUAUAUAT

UGUCUAUI

CUUGUCUZ

GUCUUGUC

UAAUG CAL

AUAAUGCP

AACAGGAL

AAACAGG.A

UAAAACAG

AUAUAUAA

GAUAUAUA

GGAUAUAUJ

UGGAUAUA

AUUGGAUA

UCALTUGGA

AUUCAUTUG

CCCAGtJUA

GCCCCAGU

UGACUCUU

AUGACUCU

UAGACCAU

CUTUUUCUA

CCCuUTUC

UACAGAGA

GUACAGAG

GGUACAGA

UGGGUACA

GAUTUUGGG

Pi CUGAUGA k. CUGAUGA J CUGAUGA

CUGAUGA

J CUGAUGA J CUGAUGA k. CUGAUGA kCUGAUGA

CUGAUGA

JCUGAUGA

LCUGAUGA

fCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA I CUGAUGA CUGAUGA CUGAUGA CUGAUGA 2, CUGAUGA Y~ CUGAUGA Y CUGAUGA Y K GAA AAAACCUG K GAA AUAAAACC K GAA AGAUAAAA.

SGAA ACUTUGAGA SGAA AUACUUGA CGAA AAUACUJG C GAA AUUAAUAC GAA AUAUUTAAU GAA AUAUAUUA GAA AGUGUCUU GAA AAGUGUCU GAA AUG CAUAA GAA AAUGCAUA GAA AUAAUGCA GAA ACAGGAUA GAA AACAGGAU GAA AAACAGGA GAA AAAACAGG GAA AUAAAACA GAA AUAUAAAA GAA AUAUAUAA GAA AUUCAUUG GAA AUAUUCAU GAA ACUCGCCC GAA AACUCGCC GAA ACUCUUAA GAA ACCAUGAC GAA AGACCAUG GAA ACCCCUUU GAA AACCCCUU GAA AAACCCCJ GAA AGAAACCC GAA ACAGAGAA GGUUUUAu(

UUUUAUCU(

UCUCAAGUI

UCAAGUAUt.

CAAGUAUUW

GUAUUAAUP

AUUAAUAIUh

UAAUAUAUP

AAGACACUU

AGACACUUA

UUAUGCAUU

UAUGCAUUA

UGCAUUAUC

UAUCCUGUU

AUCCUGUUU

UCCUGUUUU

CCUGUUUUA

UGUUUUAUA

ULJUAUAUA

UUAUAUAUC

CAAUGAAUA

AUGAAUAUA

GGGCGAGUU

GGCGAGUUA

UtJAAGAGUC

GUCAUGGUC

CAUGGUCUA

AAAGGGGUJI

AAGGGGUUU

AGGGGUUUC

GGGUUUCUC

UUCUCUGUA

UCAAGUAU

AAGUAUUA

kUUAAUAUA J AAUAUAUA

SAUAUAUAG

LUAUAGACA

LUAGACAAG

GACAAGAC

AUGCAUULA

UGCAUUAU

AUCCUGUU

CUOUJUUUA

UUAUAUAU

UAUAUAUC

AUAUAUCC

UAUAUCCA

UAUCCAAU

UCCAAUGA

CAAUGAAU

UAACUGGG

ACUGGC

AAGAGUCA

AGAGUCAU

AUGGUCUA

UAGAAAAG

GAAAAGGG

UCUCUGUA

CUCUGUAC

UCUGUACC

UGUACCCA

CCCAAAUC

CAGGUUUTUA UCUCAAGU 178 4990 ACCAGCCC CUGAUGA X GAA AUUUGGGU 4999 5029 5032 5039 5041 5044 5045 5048 10 5053 5056 5066 5074 5082 5083 5085 5087 5088 5089 20 5092 5093 5096 5103 5104 5105 5111 5122 5134 5141 5143 5151 5153 5154

AGUAACUA

IJUAGUAAC

AGUTJUAGU

UAGUUUAG

GAGUAGUU

UGGGUGAG

CUUUGGGU

GAGGUCCC

AAGCCAGU

GUAAAGAG

AGUAAAGA

GAAGUAAA

AUGAAGUA

GAUGAAGU

UGAUGAAG

CCAUGAUG

UCCAUGAU

AAAUCCAU

GAUGGUGA

GGAUGGUG

GGGAUGGU

UGCCUUGG

UCCUCUCA

AUACUCUUC

UGGGCUGA

C

UAUGGGCTJ

C

UUAAUAAA

C

GCUUAAUAC

UGCUUAATJ

CUGAUGA X CUGAUGA

X

CUGAUGA

X

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA

X

CUGAUGA X CUGAUGA X CUGAUGA

X

CUGAUGA

X

CUGAUGA

X

CUGAUGA

X

CUGAUGA

X

CUGAUGA

X

CUGAUGA

X

CUGAUGA

X

CUGAUGA

X

CUGAUGA

XC

CUGAUGA

XC

:UGAUGA XC UGAUGA X C UGAUGA

XC

.TJGAUGA

XC

UGAUGA X G ~UGAUGA XG UGAUGA

XG

UtGAUGA

XG

UGAUGA XG CUUGGUCC

CUGAUGA

GCUGGGAC

CUGAUGA

AUAGCUGG

CUGAUGA

GAA ACCAGCCC GAA ACCACUCU GAA ACAACCAC GAA AGCUGGGA GAA AUAGCUGG GAA ACUAUAGC GAA AACUAUAG GAA AGUAACUA GAA AGUUUAGU GAA AGUAGUUU GAA ACUUUGGG GAA AGGUCCCA GAA AGCCAGUG GAA AAGCCAGU GAA AGAAGCCA GAA AGAGAAGC GAA AAGAGAAG GAA AAAGAGAA :;AA AGUAAAGA .,AA AAGUAAAG 3AA AUGAAGUA 3AA AUCCAUGA ,AA AAUCCAUG ,AA AAAUCCAU ;AA AUGGUGAA ,A ACUGCCUU ,AA AGCUCCUC AA ACUCUUUA AA AUACUCUU AA AUGGGCUG AA AUAUGGGC AA AAUAUGGG ACCCAAAUC

GGGCUGGU

GGGCUGGUU

GGACCAAG

AGAGUGGUU

GUCCCAGC

GUGGUUGUC

CCAGCUAU

UCCCAGCUA

UAGUUACU

CCAGCUAUA

GUUIACUAA

GCUAUAGUU

ACUAAACU

CUAUAGUUA

CUAAACUA

UAGIJUACUA

AACUACUC

ACUAAACUA

CUCACCCA

AAACUACUC

ACCCAAAG

CCCAAAGUU

GGGACCUC

UGGGACCUC

ACUGGCUU

CACUGGCUU CUCUUtJAC ACUGGCUUC

UCUUUACU

UGGCUUCUC tJUUACUUC GCUUCUCUU

UACUUCAU

CUUCUCUUU

ACUUCAUC

UUCUCUUUA

CUUCAUCA

UCUUUACUU CAtUCAUGG CUUUACUnjC

AUCAUGGA

UACUUCAUC

AUGGAUUU

UCAUGGAUU

UCACCAUC

CAUGGAUUU

CACCAUCC

AUGGAUTUUC

ACCAUCCC

UUCACCAUC

CCAAGGCA

AAGGCAGUC

UGAGAGGA

GAGGAGCUA

AAGAGUAU

UAAAGAGUA

UCAGCCCA

AAGAGUAUC

AGCCCAUA

CAGCCCAUA

UTJUAUTJAA

GCCCAUAUU

UAUUAAGC

CCCAUAUTUU ALTUAAGCA 179

S

5155 5157 5158 5165 5166 5167 5172 5175 5195 5198 5199 5200 5209 5213 5215 5221 5227 5233 5235 20 5236 5239 5250 5273 5275 5277 5278 5280 5281 5282 5283 5286 5290 5291

GUGCUUAP

AAGUGCUU

AAAGUGCU

GGAGCAUA

AGGAGCAU

AAGGAGCA

GUGCCAAG

GCUGUGCC

GCAUAAAU

CUTJGCAUA

GCUUGCAU

AGCUITJGCA

UGGAGAGG

UAGCUGGA

CCUAGCUG

CUGAGUCC

AAUAUCCU

UUGACUAA

CALUGACU

UCAUTUGAC

GGCUCAUU

LUU.-UU

APAUAAGA

GAAAAUAA

AUGAAAAU

GAUGAAAA

CAGAUGAA

ACAGAUGA

AACAGAUG

AAACAGAU

AUGAAACA

AGGUAUGA

AAGGUAUG

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA)

CUGAUGA2

CUGAUGA)

GA-

GAP

GAP

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAA

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

AAAUAUGG

AUAAAUAU

AAUAAAUA

AGUGCUUA

AAGUGCUU

AAAGUGCU

AGCAUAAA

*AGGAGCAU

*ACACAUCA

AUUACACA

APUUACAC

AAAUUACA

AGCUUEGCA

AGGGAGCU

AGAGGGAG

AGCUGGAG

AGUCCUAG

AUCCUGAG

AUAUCCUG

APUAUCCU

ACUAAUAU

AUGGCUCA

AGGUUUUU

AUAGGULU

AGAUAGGU

APGAUAGG

AUAAGAUA

APUAAGAU

AAAUAAGA

AAAAUAAG

AUGAAAAU

ACAGAUGA

APCAGAUG

CCAUAUUU;

AUAUUUAUL

UAUUUAUU.P

UAAGCACUL

AAGCACUUL

AGCACUUU.P

UUUAUGCUC

AUGCUCCUU

UGAUGUGUA

UGUGUAAUU

GUGUAAPUU

UGUAAUUUA

UGCAAGCUC

AGCUCCCUC

CUCCCUCUC

CUCCAGCUA

CUAGGACUC

CUCAGGAUA

CAGGAUAUU

AGGAUAUTUA

AUAUUJAGUC

UGAGCCAUC

AAAAACCUA

AAACCtJAUC

ACCUAUCUU

CCUAUCUTUA

UAUCLTJAU

AUCUUAUUU

UCUJAUUUU

CUTUAUtJUUC

AUUUUTCAUC

UCAUCUGUU

CAUCUGUUUI

iUUAAGCAC

JAAGCACUU

LAGCACUUJ

FUAUGCUCC

IAUGCUCCU

UGCUCCUU

CUUGGCAC

GGCACAGC

AUTUUAUGC

UAUGCAAG

AUGCAAGC

UGCAAGCU

CCUCUCCA

UCCAGCUA

CAGCUAGG

GGACUCAG

AGGAUAUUJ

UUAGUCAA

AGUCAAUG

GUCAAUGA

APUGAGCC

AAAAGGAA

UCUUALUU

LTUALTTJUC

AtJUUUCAU

UUULJCAUC-

UUCAUCUG

UCAUCUGU

CAUCUGUU

AUCUGUU

UGUUTUCAU

UCAUACCU

CAUACCUU

180 5292 CAAGGUAU CUGAUGA X GAA AAACAGAU AUCUGU=UC AUACCUUG 5295 5299 5302 5309 5311 5331 5350 5367 5369 5370 5376 5378 5395 15 5397 5399 5408 5410 5412 20 5413 5419 5422 5432 5433 5438 5447 5448 5452 5475 5497 5504 5505

AGACAAG(

CCCCAGA(

AGACCCC2 CGUCAUUfl

AUCGUCAT

CCCAtJGUC CCCUUUTuc

ACCCCAAP

AGACCCCP

UAGACCCC

CAUCUCUA

CUCAUCUC

AUUUUAGA

CCAUtJUUA

AGCCALTTJU

UUCUAAGA

ACUUCUAA

CAACUTJCU

ACAACUUC

GCACAUAC

UUUGCACA

CAGACCAU

ACAGACCA

AGCACACA

CACGACCU

GCACGACC

GUGUGCAC

CCAGCUGU

AAAGCAGC

CUCUCCCA

GCUCUCCC

3CUGAUGA

CUGAUGA

~CUGAUGA

k. CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA 2 CUGAUGA

Y

G,~

GAj

GAJ

GA)

GA7

GA-Z

GA-Z

GAP

GA7A

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

~AUGAAACA

~AGGUAUGA

~ACAAGGUA

\ACCCCAGA

\AGACCCCA

ACCCUGUU

ACCCUGUC

AGCGGGCA

AGAGCGGG

AAGAGCGG

ACCCCAAA

AGACCCCA

ACCCAGGG

AGACCCAG

AGAGACCC

AG CCAUUUT

AGAGCCAU

AGAGAGCC

AAGAGAGC

ACUTUCUAA

ACAACUTUC

AUUUGCAC

AAUUUGCA

ACCAUAAU

AGCACACA

AAGCACAC

ACCUAAGC

ACCGGCUC

AUTUCAUCG

AGCAGCUA

AAGCAGCU

UGUUUCAU

UCAUACCU

UACCUUGU

UCUGGGGU

UGGGGUCU,

AACAGGGU

GACAGGGU

UGCCCGCU(

CCCGCUCUM

CCGCUCUUTI

LUUUGGGGU(

UGGGGUCUI

CCCUGGGUC

CUGGGUCUC

GGGUCUCUP

AAAUGGCUC

AUGGCUCUC

GGCUCUCUU

GCUCUCUUA

UUAGAAGUU

GAAGUTUGUA

GUGCAAAUU

UGCAAAUTUA

AUUAUGGUC

UGUGUGCUU

GUGUGCUUA

GCUUAGGUC

GAGCCGGUC

CGAUGAAUA

UAGCUGCU

AGCUGCLUU

A CCUUGUCU U GUCUGG C UGGGGUCU C UAAUGACG

AUGACGAU

GACAUGGG

k. GAAAAGGG 2 UUUGGGGu J UGGGGUCU

JGGGGUCUA

7UAGAGAUG

GAGAUGAG

UCUAAAAU

UAAAAUGG

LAAAUGGCU

UCUUAGAA

UUAGAAGU

AGAAGUUG

GAAGUUGU

GUAUGUGC

UGUGCAAA

AUGGUCUG

UGGUCUGU

UGUGUGCU

AGGUCGUG-

GGUCGUGC

GUGCACAC

ACAGCUGG

GCUGCUU

UGGGAGAG

5524 UAAGUGGC CUGAUGA X GAA AGCAUGCU AGCAUGCUA GCCACUUA 181 0 0.0.

*0 S 0 0 fr000 0000 ~0 0*0* *0*e 5531 5532 5535 5536 5538 5554 5561 5568 5577 5584 5587 5588 5593 5594 15 5.595 5596 5600 5627 5660 5662 5671 5685 5693 5704 5705 5707 5731 5736 5754 5756 5757 5760 5764

AGAGAAU

CAGAGAAI

GGUCAGA(

CGGUCAGA

CCCGGUCa

GUACCCAI

GGAGCAGC

ACACAGG(

GGAUGGGC

ACCUTUAAC

AAAACCUL

GAAAACCL

AGACAGAP

CAGACAG.A.

UCAGACAG

AUCAGACA

UCUCAUCA

UCAGUGGG

UGCACCAA

AGUGCACC

UGGCUGGU

UACUUGUC

CCCULJUCC

GUGGCUAG

UGUGGCUA

AGUGUGGC

CCCUACCU

GCCAG CC C

UGGACAAA~

AAUGGACA

GAAUGGAC

UGCGAAUG

CtUUU)TGCG U CUGAUGA UT CUGAUGA 3 CUGAUGA

CUGAUGA

CUGAUGA

J CTJGAUGA 3 CUGAUGA

;CUGAUGA

CUGAUGA

CUGAUGA

SCUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA2

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA I CUGAUGA2

CUGAUGA)

CUGAUGA

CUGAUGA 2 CUGAUGA Y CUGAUGA y~ CUGAUGA Y K GAA AGUGGCUA K GAA AAGUGGCU .K GAA AUTUAAGUG K GAA AAUTUAAGU K GAA AGAAUUAA C GAA AUG CUGOC C GAA ACCCAUGA I GAA AGCAGGUA CGAA ACACAGGG GAA AUGGGGUA GAA AGGAUGGG GAA AAGGAUGG GAA ACCUAAG GAA AACCUUAA GAA AAACCUtJA GAA AAAACCUU GAA ACAGAAAA GAA AUtJGCACU GAA AGCCACAG GAA AGAGCCAC GAA AGUGCACC GAA AGUCCUGG GAA ACUUGUCU GAA AGCCCUUU GAA AAGCCCUU GAA AGAAGCCC GAA AUUUUCUU GAA ACCUGALU GAA AUGUCUUU GAA AGAUGUCU GAA AAGAUGUC GAA ACAAAGAU GAA AUGGACAA

UAGCCACUI

AGCCACUU)

CACLTUAAL71

ACLTUAAUTUC

UUAALTUCUC

GCCAGCAUC

UCAUGGGUP

UACCUGCUC

CCCUGUGUP

UACCCCAUC

CCCAUCCUU

CCAUCCUTUA

CUUAAGGUU

UUAAGGUU

UAAGGUUUU

AAGGUUUUC

UUTUUCUGUC

AGUGCAAUC

CUGUGGCUC

GUGGCUCUU

GGUGCACUC

CCAGGACUA

AGACAAGUA

AAAGGGCUU

AAGGGCUUC

GGGCUUCUA

AAGAAAAUC

AAUCAGGUA

AAAGACAUC

AGACAUCTU

GACAUCUUU

AUCUUUGUC

UUGUCCALU

J AAtJUCUCU k. AUUCUCUG J CUCUGACC

UCUGACCG

UGACCGGG

AUGGGUAC

CCUGCLTCC

CCCUGUGU

CCCC.AUCC

CUUAAGGU

AAGGUUUU

AGGUUUTUC

UUCUGUCU

UCUGUCUG

CUGUCUGA

UGUCUGAU

UGAUGAGA

CCCACUGA

UUGGUGCA

GGUGCACU

ACCAGCCA

GACAAGUA

GGAAAGGG

CUAGCCAC

UAGCCACA

GCCACACU

AGGUAGGOG

GGGCUGGC

UUUTGUCCA

UGUCCAUU

GUCCAUUTC

CAUUCGCA

CGCAAAAG

182 Ib Ce C see.

0

C

C,

C C

S.

C C eC.

ec C C

Q

4

C

ewe.

*CO*

CC

C. 0

C

cc..

-eec..

C

e.e.c.

C

5765 5775 5777 5780 5794 5798 5818 5852 5853 10 5854 5856 5859 5865 5867 15 5875 5896 5903 5908 5910 20 5911 5913 5914 5919 5920 5921 5922 5925 5928 5930 5933 5934 5940 5943

GCUUUEJG

GCCGACA

CAGCCGA

CUGC-AGC

GCCUGAC

CAtJCGCCI

UUCUCUG(

GGAUGAGJ

UGGAUGA(

CUGGAUG)

AUCUGGAI

GAUAUCUC

UUGCUGG7

AALJUGCUC

CACCC CC C

GGACCAUC

UAAUACAG

CGGAAUAA

AUCGGAAU

AAUCGGAA

AAAAUCGG

UAAAAUCG

AUTUAUUAA

GAUEJAUUA

AGAUUAUU

UAGAUUAU

AAUUAGAU

ACGAAUTUA

UCACGAAU

UGAUCACG

AUGAUCAC

CUCUUAAU

AGUCUCUU

C CUGAUGA A CUGAUGA C CUGAUGA C CUG AUGA LU CUGAUGA LI CUGAUGA 3CUGAUGA

~CUGAUGA

3 CUGAUGA k~ CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I

CUGAUGA)

CUGAUGA)

CUGAUGA CUGAUGA CUGAUGA

Y~

CUGAUGA

Y

CUGAUGA

X

CUGAUGA

X

CUGAUGA

X

CUGAUGA X CUGAUGA X X GAA AAUGGACA X GAA AGCUUUTUG X GAA AGAGCUUU X GAA ACAAGAGC X GAA ACACACUG X GAA ACUUACAC K GAA AGCCUCUG K GAA ACCUCAGG K GAA AACCUCAG GAA AAACCUCA CGAA AGAAACCU C GAA AUGAGAAA IGAA AUCUGGAU GAA AUAUCUGG GAA AUUGCUGG GAA AUGGUCUU GAA ACCAUCUA GAA ACAGGACC GAA AUACAGGA GAA AAUACAGG GAA AUAAUACA GAA AAUAAUAC GAA AUCGGAAU GAA AAUCGGAA GAA AAAUCGGA GAA AAAAUCGG GAA AUUAAAAU GAA AUUAUUjAA GAA AGAIJUAUU GAA AUUAGAtU GAA AAUUAGAU GAA AUCACGAA GAA AUGAUCAC UGUCCAUUC

GCAAAAGC

CAAAAGCUC

UUGUCGGC

AAAGCUCULJ GUCG4GCUG GCUCUUGUC

GGCUGCAG

CAGUGUGUA

AGUCAGGC

GUGUAAGUC

AGGCGAUG

CAGAGGCUA

CCAGAGAA

CCUGAGGUU

UCUCAUCC

CUGAGGUUTU

CUCAUCCA

UGAGGUUUC

UCAUCCAG

AGGUUtUCUC

AUCCAGAU

UUUCUCAUC

CAGAUAUC

AUCCAGAUA

UCCAGCAA

CCAGAUAUC

CAGCAAUU

CCAGCAAUU

GGGGGGUG

AAGACCAUA

GAUGGUCC

UAGAUGGUC

CUGUAUUA

GGUCCUGUA

UUAUUCCG

UCCUGUAULJ

AUUCCGAU

CCUGUAUUA

UUCCGAUU

UGUAUUJAUU CCGAtUtJU GUAUTUAUTUC CGAtTUUUA AUEJCCGAUU tTUAAUAAU UUCCGA1JtTJ

UAAUAAUC

UCCGAUUUU

AAUAAUCU

CCGAUUJUA

AUAAUCUA

AULUUAAUA

AUCUAAUU

UTUAAUAAUC

UAAUTJCGU

AAUAAUCUA

AUUCGUGA

AAUCUAAUU

CGUGAUCA

AUCUAAUUC

GUGAUCAU

UUCGUGAUC AUEJAAGAG GUGAUCAUU AAGAGACU 183

I

5944 5952 5953 5954 5957 5963 5967 5968 5969 10 5970 5981 5992 5994 6000 6001 6003 6008 6009 6014 20 6015 6022 6023 6027 6028 6036

AAGUCUCU

AUUtJACUA

CAUIJUACU

ACAUTUUAC

GGGACAUU

GGAAAAGG

UGUGGGAA

UIJGUGGGA

LUUGUGGG

UULJUGUGG

CUUTiuCUrj

AAUCCCGA

AGAAUCCC

AACCAGAG

GAACCAGA

CAGAACCA

UUAAGCAG

UUtJAAGCA

AAGUCUTU

UAAGUCU

CCAAAGCU

UCCAAAGC

AGGCUCCA

UAGGCUCC

AACUUUCA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA2

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA:

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

AAUGAUCA

AGUCUCUU

AAGUCUCU

AAAGUCUC

ACUAAAGU

ACAUUUAC

AGGGACAU

AAGGGACA

AAAGGGAC

AAAAGGGA

ACUIJUUGU

AGCUUUUC

AUAGCUUU

AUCCCGAU

AAUCCCGA

AGAAUCCC

ACCAGAGA

AACCAGAG

AGCAGAAC

AAGCAGAA

AGUCUUTUA

AAGUCUUU

AGCUAAGU

AAGCUAAG

AGGCUCCA

ACUUUCAU

UGAUCAUUIA

AAGAGACUU

AGAGACLUU

GAGACUUA

ACUUUAGUA

GUAAAUGUC

AUGUCCCUU

UGUCCCUUU

GUCCCUUU

UCCCUUJUC

ACAAAAGUA

GAAAAGCUA

AAAGCUAUC

AUCGGGALU

UCGGGAUUC

GGGAUUCUC

UCUCUGGUU

CUCUGGUUC

GUUCUGCUU

UUCUGCUUA

UAAAGACU

AAAGACUUA

ACUTUAGCLU

CUTUAGCUU

UGGAGCCUA

AUGAAAGUU

AGAGACUU

UAGUAAAU

AGUAAAUG

GUAAAUGU

AAUGUCCC

CCUUIJUCC

LJUCCCACA

UCCCACAA

CCCACAAA

CCACAAAA

AAGAAAAG

UCGGGAUU

GGGAUTUCU

CUCUGGUU

UCUGGUUC

UGGIJUCUG

CUGCUTUAA

UGCLUAAA

AAAGACUU

AAGACUUA

AGCUUUGG

GCIJGGA

UGGAGCCU

GGAGCCUA

UGAAAGUU

GAUCAGCC

6044 GGCUGAUC CUGAUGA X Where I"X" represents stem II region of a HH ribozyme (Hertel et al., 1992 Nucleic Acids Res. 20 3252).

may be a 2 base-pairs.

The length of stem II C 9* C C C Ge C. C C C C C C C C a. C C

C

184 Table IX: Mouse fill VEGF Receptor-Hairgin Ribozvme and Substrate Seauence nt.

Posi tion HP Ribozyme Sequence Substrate 33 36 67 79 166 197 214 266 487 501 566 640 691 703 GUCCCAGC AGAA GACCAU ACCAGAGAAACACACGJUGUGGUACAUIJACCUGGUA

GGUGUCCC

UAAGGCAA

GACACCCG

CUGUGAGA

GAAAGAGA

CAUGAGUG

CGGUCGUG

CUCCCACA

CGAUGAUG

CC UCA CC C

CUUUGCCC

CGCAGUUC

GCCGAUGG

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCUGAC

GCGGUG

CCGCGU

GACACC

GGCCUG

GCCUCC

GAGACC

GAUGGG

GUCUUC

GGGGAU

GGGGUA

GUCCUA

GAUAGU

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUACCUGGUA

ACAAAAAAGUGGUCUACGU

ACCAGAGAAACACACGUUGUGGUACAUUrACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGJIGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGJTUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGTJUGUGGUACAUPJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAIJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

AUGGUCA

GUCAGCU

CACCGCG

ACGCGCU

GGUGUCU

CAGGCCA

GGAGGCA

GGUCUCU

CCCAUCG

GAAGACA

AUCCCCU

UAC C CCU

UAGGACU

ACUAUCU

GCU

GCU

GUC

GCU

GCU

GAC

GCC

GCC

GCC

GCU

CC

GAU

GCU

GCUGGGAC

GGGACACC

TJUGCCUUA

CGGGUGUC

UCUCACAG

UCUCIJTUC

CACUCAUG

CACGACCG

UGUGGGAG

CAUCAUCC

GGGUGACG

GGGCAAAG

GAACUGCG

UUGUAUUG AGAA GCCGAU ACCAGAGAAACACACGJUGUGGUACAUUTACCUGGUA AUCGGCA GAC CAAUACAA V e 0 0 0 0 Vea 0 0 0 a 185 736 754 766 871 960 988 1051 1081 1090 1093 1169 1315 1363 1604 1612 1629 1632 1688 1730

CUGGGCUC

GCCCGUGG

GGACAAGA

UCCGGUCA

CUUCACGC

UGUUGAAA

CCUGCACC

GCCGAUAG

UCAUGGAC

CUUUCAUG

AAAUAGCG

TJUUCGUAG

UGCUGCCC

GUCUGAGA

UUCCAGGG

GGCCCGGC

GAAGGCCC

UUCGGCAC

UCUCCUUC

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

*GGCGUA

*GUCUCA

GCCCGU

GCUGCC

GGUGUA

GGAACG

GCUUCC

GUCUUC

GAUAGG

GCCGAU

GACUUC

GAGGUU

GAUAGA

GCCACC

GAGAGU

GUAGAU

GCUGUA

GUGACA

GGCAUC

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGIJTGUGGUACAUUtACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUIJGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUTJACCUGGUA

ACCAGAGAAA.CACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAA~CACACGUJTGUGGUACAUUACCUGGUA

ACCAGAGAACACACGUUTGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJTGUGGUACAUUrACCUGGUA ACCAGAGAAP.CACACGUUJGUGGUACAU1JACCUGGUA

ACCAGAGAACACACGUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA

ACAAAAAAGnGGUCUACGU

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCIJGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

UACGCCC GCC GAGCCCAG UGAGACU GCU CCACGGGC ACGGGCA GAC UCUUGUCC GGCAGCG GAU UGACCGGA UACACCU GUC GCGUGAAG CGUUCCA GUC UUUCAACA GGAAGCA GCC GGUGCAGG GAAGACG GUC CUAUCGGC CCUAUCG GCU GUCCAUGA AUCGGCU GUC CAUGAAAG GAAGUCU GCU CGCUAUUU AACCUCA GAU CUACGAAA UCUAUCC GCU GGGCAGCA GGUGGCU GAC UCUCAGAC ACUCUCA GAC CCCUGGAA AUCUACA GCU GCCGGGCC UACAGCU GCC GGGCCUUC UGUCACA GAU GUGCCGAA GAUGCCA GCC GAAGGAGA Al

A

S.

S

S

5~* S S S S 55

S

S. S S S S S S

SSS

SSS 55 5-5 5 5 0 *S 0 55 05 55 5 55 S S S S S S S S *5 S S *5S

S

186 1753 2017 2101 2176 2258 2305 2383 2405 2 432 2464 2467 2592 2596 2653 2743 2779 2814 2831

CCACACAG

GGUU1JUGA

ACCAAGUG

UUUCAAUA

GUGAGGUA

UGAGCGUC

CGGAAGAA

GACAGGUA

C GAA CUU C

CAUACGGC

CAUCAUAG

CACAGUCC

CAGCCACA

GUUCCGUC

CGAUCACC

GCUAGUUG

CUUGUUGA

AUAUGCAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GUUUCA

GGUGUG

GAGGCG

GCGUGC

GCGCUU

GCUCCA

GCUUCA

GUCUUU

GGGUCC

GUUCAC

GCCGUU

GGUGGG

GGCAGG

GAGCUU

GAGGCC

GGUUTUC

GAAUAA

GCGUCC

ACCAGAGAAACACACGJUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJIGUGGUACAtPJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCACAGAAACACACGUUGUGGUACAUJIACCUGCUA

ACCAGAGAAACACACGUJGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUJCUCGUACAUJTACCUCCUA

ACCAGAGAAACACACGUJIGUGGUACAUUACCUCGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCACAGAAACACACGUJIGUGGUACAUUACCUGGUA

ACCAGAGAATACACACGUUGUGGUACAU1JACCUGGUA

ACCAGAGAAACACACGIJUGUGGUACATJUACCUGGUA

ACCAGAGAAACACACGUIJCUGGUACAUJTACCUGCUA

ACCACAGAAACACACGUUGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUJGUGUACAUJTACCUGGUA

ACCACAGAAACACACGUJGUGGUACAUJTACCUGGUA

UCAAACU

CACACCU

CCCCUCA

GCACGCU

AACCA

UCGAGCU

UCAAGCG

AA.AGACA

GGACCCA

GUGAACG

AA CCG CU

CCCACCU

CCUCCCG

AAGCUCU

GGCCUCU

CAAACCU

UIUAUUCU

GGACGCA

GUC

GCU

GAU

Cl-n

GCC

GAU

GUC

GAC

GAU

CCU

CC

G0CC

GAC

GAU

CAU

GUC

GUC

CUGUCUCC

UCAAAACC

CACUUCCU

UAUUCAAA

UACCUCAC

CACCCUCA

UUCUUCCG

UACCUCUC

CAACUUCC

CCCCUAUC

CUAUCAUC

CCACUCUC

UCUCCCUC

CACCGAAC

CCUCAUCG

CAACUACC

UCAACAAC

UUGCAUAU

-I 2895 295 ACUGUCUA AGAA GGGCUU ACCAGAGAAACACACGUUGUGGUACAUUTACCUGCUA AAGCCCC CCC UAGACAGU

S

S S S S S S S S S

S

187 2913 GACACUUG AGAA GCUGAC ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA GUCAGCA GCU CAAGUGUC 2928 2934 3001 3022 3033 3064 3179 3357 3360 3379 3463 3496 3553 3615 3623 3650 3754 3772

GAAGCUGG

UUCAGGGA

UGGUGAGG

UGUAGGAA

CACUUGGA

UUCUGGAG

CUCACAUA

CUUCAGGC

UUCCUUCA

GGGUUCUC

GUUCAGCA

UGGCIJUGA

UGUUUCUA

AUCUGCAA

AAAUGUGG

CUCACAUC

UAGUGUCC

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GGUGAC

GGAGCU

GCUUGO

GGUCUU

GUAGGA

GAAACU

GGGUUC

GCAGAA

GCUGCA

GCAUGC

GGGGCC

GGUCAC

GUAUGG

GUCCUU

GCAAAG

GAGCUU

GAUAGU

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUrJACCUGGUA ACCAGAGAAACACACGUrJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGIJUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACIJUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACATJIJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUrACCUGGUA ACCAGAGAAA.CACACGUUGUGGUACAUUtACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUIACCUGGUA

GUCACCA

AGCUCCA

CCAAGCA

AAGACCU

UCCUACA

AGUUUCU

GAACCCU

UUCUGCA

UGCAGCC

GCAUGCG

GGCCCCG

GUGACCU

CCAUACU

AAGGACG

CUUUGCA

AAGCUCU

ACUAUCA

GCU

GCU

GCC

GAU

GUU

GUC

GAU

GCC

GCC

GAU

GUU

GCU

GAC

GCU

GAU

GAU

GCU

CCAGCUUC

UCCCUGAA

CCUCACCA

UUCCUACA

UCCAAGUG

CUCCAGAA

UAUGUGAG

GCCUGAAG

UGAAGGAA

GAGAA C CC

UGCUGAAC

UCAAGCCA

UAGAAACA

UUGCAGAU

CCACAUUU

GAUGUGAG

GGACACUA

GGGAGCCC AGAA GAGUGC ACCAGAGAAACACACGUUGUGGUACAUUIACCUGGUA GCACUCU GCU GGGCUCCC 0 0* 04 4 *0s 4** 0 0* 0** 0 00 0 0 00 4 000 4* 0 000 00* .0 4* 0 0 0V 188 3796 3881 3886 3897 3903 3912 3969 3972 3986 4018 4022 4040 4053 4095 4110 4113 4168 4290 4294

UCCAGGUG

CUCGGCAG

UGGGCCUC

GAAGCAGA

GCUGGAGA

GUGGCCAC

UGGAGAAC

GGGUGGAG

GAGUUGUA

UUUAGGCG

AAGCUUUA

GUUGUCGG

CUGUCAGG

UCCUGUGG

CGAAAAGC

UCACGAAA

UTUAGUCAA

GGUGGGCG

GGCCGGUG

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCUUCA

GAAAGU

GAUCGG

GGGCCU

GAAGCU

GGAGAA

GGACUC

GCAGGA

GGGGGU

GGGAGG

GGCGGG

GGUGAG

GGUUGU

GAAUAG

GGCUCC

GCUGGC

GCAACA

GUCGCC

GGCGGU

ACCAGAGAAACACACGUUTGUGGUACAJTUACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUrACCUGGUA

ACCAGAGAAACACACGU!JGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUTJGUCGUACAUUACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAAACACAGUUIGUGGUACAUU1ACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJTGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUUrGUGGUACAUTJACCUGGUA ACCAGAGACACACAGUUrGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

UGAAGCG

ACJUCC

CCGAUCU

AGGCCCA

AGCUUCU

UUCUCCA

GAGUCCU

UCCUGCU

ACCCCCA

CCUCCCC

CCCGCCC

CUCACCA

ACAACCA

C UAUUC C

GGAGCCA

GCCAGCU

UGUUGCU

GGCGACC

ACCGCCC

GUU

GAU

GCC

GCU

GCU

GCU

GCU

GUU

GAC

GCC

GCC

GCC

GCC

GCU

GCU

GCU

GUU

GCC

GCC

CACCUGGA

CUGCCGAG

GAGGCCCA

UCUGCUUC

UCUCCAGC

GUGGCCAC

GUIJCUCCA

C UC CACC C

UACAACUC

CGCCUAAA

UAAAGCUU

CCGACAAC

CCUGACAG

CCACAGGA

GCUIJUUCG

UUUCGUGA

UUGACUAA

CGCCCACC

CACCGGCC

'16 0~ 0* 900 000 0 0 0 0 *0 00 a.0 0 0 0. 0 0 00 00 0 o 00 1 0 0 189 4329 4378 4383 4388 4457 4525 4528 4643 4650 4724 4771 4785 4809 4834 4912 5119 5144 5287

AGUCCCAC

CAGAGCAG

AGAGACAG

AUAAGAGA

CUCCACAG

CCCGAAAC

GGGCCCGA

AAACAGAC

GGAUGGUA

ACUAGAGG

AUGCGAAG

UCCCCGUG

CUAGGCCA

UUGAGCCC

AUAUAUAA

UCCUCUCA

UAAAUAUG

AGGUAUGA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCAGGG

GUGCAU

GGUCAG

GAGCAG

GACGCA

GAGGCC

GCGGAG

GAAGAC

GACAAC

GAUGA)

GGCCUG

GUAUGC

GGACCA

GUAGGC

GGAUAA

GCCUUG

GAUACU

GAUGAA

ACCAGAGAA-ACACACGUJGUGGUACAUrJACCUGGUA

ACCAGAGAAACACACGU)GUGGUACAUIJACCUGGUA

ACCAGAGAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUJTGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUrACCUGGuA

ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAJIUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJIACCUGGUA

ACCAGAGAAA~CACACGU1JGUGGUACAUyJACCUGGUA ACCAGAGAAACACACGUUGUGGUACAUUrACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

CCCUGCA

AUGCACU

CUGACCU

CUGCUCU

UGCGUCC

GGCCUCC

CUCCGCU

C UC UUC U

GUUGUCU

AUCAUCA

CAGGCCU

GCAUACU

UGGUCCA

GCCUACU

UUAUCCU

CAAGGCA

AGUAUCA

UUCAUCU

GCU

GAC

GCU

GUC

GUC

GUT)

GUT)

GUT)

GAC

GCU

GLU

GAT)

GUT)

GUC

GCC

GUGGGACU

CUGCUCUG

CUGUCUC)

UCUCUUAU

CUGUGGAG

GUUUCGGG

UCGGGCCC

GUCUGULU

UACCAUCC

CCUCUAGU

CUUCGCAU

CACGGGGA

UGGCCUAG

GGGCUCAA

UUAUAUAU

UGAGAGGA

CAUAUUUA

I'

5363 563 CCCCAAAG AGAA GGCACC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GGUGCCC GeT) CUUUGGGG 191 Table X: Homologous Hammerhead Ribozyme Target Sites Between Human fit-i and KDR RNA C.

C

fl

C.

a

C

a. a nt.

Position 3388 2174 2990 2693 10 2981 1359 3390 3391 2925 15 7140 1785 2731 3974 6590 6705 974 1872 2333 2775 3533 3534 3625 1814 2744 2783 ACGUGGU U UAUUUCU A CAAUAAU A GAGACUUJ A GAUGACU A LTUJAAUGU A GCCAUUU A GUCAAAU U AUAAAGU U ACUUGGU U AAGUGGU U UuUccU U UCUCCUU A GUACUCU A AGCACCU U

AACCUGC

GUCAUGA

GAAGGAA

AACUGGG

CCAGGGC

GAAAGAA

UGACAAA

ACUTUAGA

GGGACUG

UAAAAAC

CAAGCAU

AGGUGGG

GGUGGGU

CUCCUGA

GGUUGUG

fit-1 Target Sequence CCGGGAU A UIJUAUAA AAUGUAU A CACAGGG UGCAAAU A UGGAAAU CUCCCLJ A UGAUGCC GLUJGAAU A CtJGCAAA UAUGGUU A AAAGAUG GGGAUAU U UAUAAGA GGAUAUTU U AUAAGAA nt. KDR Posi- Target Sequence t ion 3151 3069 2756 2459 2747 2097 3153 3154 2691 2340 1515 768 1466 2603 3227 147 1602 1088 1745 3296 3297.

4054 1059 147 796

CCGGGAU

AgUGUAU

UGCAAAU

CUgCCTU GUgGAAU UgUGGJU

GGGAUAU

GGAUALU

AuGUGGU UAcUUtCU CucUAAU uuGACUIJ GAgGACU aaAAUGU aCaAUU uUCAAAU AcAAAGU AaaUGGU AcaUGGU UUUtJCCU UuUCCUU GagCUCU AGuACCU uu.CAAAU gAAGCAU A UUIJAUAA c CACAGGG u UGGAAAc A UGAUGCC u CLTGCAAA u AAAGAUa U UAUAAag U AUAAagA c AACCUuC u GUCAUcA u GAAGGAA c AACUGGG u CCAGGGa u GAAAGAA u UGACAgA U ACUUgcA GGGAgaG a UAAAAAu a CAAGCuU U AGGUGcu A GGUGcuU c CUCCUGu U GGIJUacc u ACUUGcA C AGCAUaa GGCAAAU C ACUEJGGA CAAGCAU C AGCAUUU 192

S

0 3613 4052 5305 7158 1836 2565 4250 7124 436 10 2234 2763 4229 5301 6015 6095 6236 5962 7629 GAGAGCU C CUGAGUA.

AAGGCCU C GCUCAAG UCUCCAU A UCAAAAC AUGUATJU U UGUAtJAC CUAGAAU U UCUGGAA CUCUCUJ C UGGCUCC CUGUACU C CACCCCA ACAUGGU U UGGUCCU AUGGUCU U UGCCUGA GCACCAU A CCUCCIJG GGGCUUU U GGAAAAG CCAGACU A CAACUCG GUUUUCU C CAUAUCA AGAAUGU A UGCCUCU AUIJCCCU A GUGAGCC UGUUGUJT C CUCUUtCU GCUUCCU U UUAUCCA UAUAUAU U CUCUGCU 1923 456 631 1007 2328 3388 3778 1337 1344 990 767 3307 1917 1438 76 3099 3096 ucuGCCU ggUCCAU gUcUAUU allgGAAU uguUCUU uUaUACU cagUGGU AcGGUCU augCCAU uuGCUUU auuGACU ugcUUCU Acu.AUGU AUaCCCU UagUGUU auaUCCU gAaAUAU

GCUCAAG

u UCAAAUC a UGUAcAu c IJCUGGug C UGGCUaC a CACCagA a UGGUuCU a UGCCauu u CCUCCCC U GGAAguG u CAACUgG C CAUAUCc c UGCCUug u GIJGAaga u CUCUt~ga c UUtAUCgg cCUCUuaU 2968 GgaAGCU C CUGAagA.

Lowercase letters are used between flt-1 and KDR RNA to represent sequence variance 193 Table XI: 2.5 umol Reagent Phosphoramidites S-Ethyl Tetrazole Acetic Anhydride N-Methyl Imidazole

TCA

Iodine Acetonitrile RNA Synthesis Cycle Equivalents Amou 6.5 163gi 23.8 238pi 100 233 186 233 83.2 -1.73 8.0 1.18 NA 6.67 nt

L

L

mL pL MnL Wait Time* 5 sec 5 sec 21 sec 45 sec

NA

Claims (19)

1. Nucleic acid molecule -which 'modulates the synthesis, expression and/or stability of an mRNA encoding one or more receptors of vascular endothelial growth factor.

2. The nucleic acid of claim 1, wherein said receptor is flt-i, KDR and/or flk-i.

3. The nucleic acid of claim 1 or 2, wherein said molecule is an enzymatic nucleic acid molecule.

4. The nucleic acid molecule~of claim 3, wherein, .the binding arms of said enzymatic nucleic acid contain sequences complementary to the substrate nucleotide base sequences in any one of Tables II to IX. The nucleic acid molecule of claims 3 or 4, *15 wherein said nucleic acid molecule is in a hammerhead ****motif.

6. The enzymatic nucleic acid molecule of claim 3 or 4, wherein said nucleic acid molecule is in a hairpin, hepatitis Delta virus, group I intron, VS nucleic acid or RNaseP nucleic acid motif.

7. The enzymatic nucleic acid molecule of any of claims 3 or 4, wherein said ribozyme comprises between 12 and 100 bases complementary to the RNA of said region.

8. The enzymatic nucleic acid of claim 7, wherein said ribozyme comprises between 14 and 24 bases comple- mentary to the RNA of said region.

9. Enzymatic nucleic acid molecule consisting essentially of any ribozyme sequence selected from those sh6wn in Tables II to IX. A mammalian cell including a nucleic acid molecule of any of claims 1, 2 or 3.

11. The cell of claim 10, wherein said cell is a human cell.

12. An expression vector comprising nucleic acid encoding the nucleic acid molecule of any of claims 1, 2, 3 or 4, in a manner which allows expression and/or delivery of that RNA molecule within a mammalian cell. ooooo

13. The expression vector of claim 12, wherein said nucleic acid is an enzymatic nucleic acid. S14. A mammalian cell including an expression vector of any of claims 12 or 13. The cell of claim 14, wherein said cell is a human cell. go S

16. A method for treatment of a patient having .a condition associated with the level of flt-l, KDR and/or fIk-l, wherein the patient, tissue donor or population of corresponding cells is administered a therapeutically effective amount of an enzymatic nucleic acid molecule of claims 1, 2, 3 or 4.

17. A method for treatment of a condition related to the level of flt-l, KDR and/or flk-l activity by adminis- tering to a patient an expression vector of claim 12.

18. The method of claims 16 or 17, wherein said patient is a human.

19. The nucleic acid of claim 1 or 2, wherein said molecule is an antisense nucleic acid molecule. 196 The nucleic acid molecule of claim 19, wherein, said antisense nucleic acid contain sequences comple- mentary to the substrate nucleotide base sequences in any one of Tables II to IX.

21. An expression vector comprising nucleic acid encoding the antisense nucleic acid molecule of any one of claims 19 or 20, in a manner which allows expression and/or delivery of that antisense RNA molecule within a mammalian cell. 10 22. A mammalian cell including an expression vector of claim 21.

23. The cell of claim 22, wherein said cell is a human cell. *N a *•g o*ooo •oe*\ 197 1. A nucleic acid molecule which modulates synthesis, expression and/or stability of an mRNA encoding flt-I receptor of vascular endothelial growth factor. 2. The nucleic acid molecule of claim 1 which specifically inhibits said synthesis, expression and/or stability.

53. The nucleic acid molecule of claim 1 or claim 2 wherein said nucleic acid molecule is an enzymatic nucleic acid molecule or an antisense nucleic acid molecule. 4. The nucleic acid molecule of any one of claims 1 to 3 wherein said vascular endothelial growth factor is human or mouse vascular endothelial growth factor. The nucleic acid molecule of claim 3 wherein said nucleic acid molecule is an 1o enzymatic nucleic acid molecule. 6. The nucleic acid molecule of claim 5 wherein said enzymatic nucleic acid ooooo molecule comprises binding arms containing sequences complementary to substrate nucleotide base sequences in any one of Tables II to IX. 7. The nucleic acid molecule of claim 6 wherein said sequences are complementary to substrate nucleotide base sequences in any one of Tables II, III, VIII and IX. 8. The nucleic acid molecule of claim 6 or 7 wherein said sequences are complementary to a substrate nucleotide base sequence of any one of SEQ ID NOS: r• 1456-2886, SEQ ID NOS: 2983-3078, SEQ ID NOS: 7223-8166 and SEQ ID NOS:

8292-8416. 9. The nucleic acid molecule of claim 8 wherein said sequences are complementary to a substrate nucleotide base sequence of any one of SEQ ID NOS: 1481-1482, 1493, 1574, 1664, 1669, 1838, 1847, 1913, 1933, 1974, 1984, 1997, 1999, 2000, 2025, 2130, 2382 or 2394. 10. The nucleic acid molecule of any one of claims 5 to 9 wherein said nucleic acid molecule is in a hammerhead motif. 11. The nucleic acid molecule of any one of claims 5 to 9 wherein said nucleic acid molecule is in a hairpin, hepatitis Delta virus, group I intron, VS nucleic acid or RNase P nucleic acid motif. 12. The nucleic acid molecule of any one of claims 1 to 9 wherein said nucleic acid molecule comprises between 12 and 100 bases complementary to the RNA encoding the fit-I receptor. 198 13. The nucleic acid molecule of claim 12 wherein said nucleic acid molecule comprises between 14 and 24 bases complementary to the RNA encoding the flt-l receptor. 14. An enzymatic nucleic acid molecule consisting essentially of any ribozyme sequence selected from those shown in Tables II to IX. The enzymatic nucleic acid molecule of claim 14 wherein said ribozyme sequence is selected from those shown in Tables II, III, VIII and IX. 16. The enzymatic nucleic acid molecule of claim 14 wherein said ribozyme sequence is any ribozyme sequence selected from SEQ ID NOS: 25-1455, SEQ ID NOS: 0io 2887-2982, SEQ ID NOS: 6279-7222 and SEQ ID NOS: 8167-8291. 17. The enzymatic nucleic acid molecule of claim 14 wherein said ribozyme ooo i sequence is any ribozyme sequence selected from the group consisting of SEQ ID NOS: 50-51, 62, 143, 233, 238, 407, 416-417, 482, 502, 543, 553, 566, 568-569, 574, 594, 699, 951 and 963. 18. A mammalian cell including a nucleic acid molecule of any one of claims 1 to 19. The mammalian cell of claim 18 wherein said mammalian cell is a human cell. An expression vector comprising nucleic acid sequence encoding the nucleic acid molecule of any one of claims 1 to 9 in a manner which allows expression and/or delivery of that nucleic acid molecule within a mammalian cell. 21. The expression vector of claim 20 wherein said nucleic acid molecule is an enzymatic nucleic acid. 22. A mammalian cell including an expression vector of claim 20 or claim 21. 23. The mammalian cell of 22 wherein said mammalian cell is a human cell. 24. The nucleic acid molecule of claim 3 wherein said nucleic acid molecule is an antisense nucleic acid molecule. The nucleic acid molecule of claim 24 wherein said antisense nucleic acid molecule contains sequences complementary to substrate nucleotide base sequences in any one of Tables II to IX. 26. The' nucleic acid molecule of claim 25 wherein said sequences are complementary to the substrate nucleotide base sequences in any of Tables II, III, VIII and IX. 27. The nucleic acid molecule of claim 25 wherein said sequences are complementary to a substrate nucleotide base sequence of any one of SEQ ID NOS: 199 1456-2886, SEQ ID NOS: 2983-3078, SEQ ID NOS: 7223-8166 and SEQ ID NOS: 8292-8416. 28. The nucleic acid molecule of claim 27 wherein said sequences are complementary to a substrate nucleotide base sequence selected from the group consisting of SEQ ID NOS: 1481-1482, 1493, 1574, 1664, 1669, 1838, 1847, 1913, 1933, 1974, 1984, 1997, 1999, 2000, 2025, 2130, 2382 and 2394. 29. An expression vector comprising nucleic acid sequence encoding the antisense nucleic acid molecule of any one of claims 24 to 28, in a manner which allows expression and/or delivery of that nucleic acid molecule within a mammalian cell. 30. A mammalian cell including the expression vector of claim 29. 31. The mammalian cell of claim 30 wherein said mammalian cell is a human ooooo .0,cell. 32. A method of cleaving RNA of fit-i gene comprising the step of contacting said RNA with the enzymatic nucleic acid molecule of claim 4 under conditions suitable for the cleavage of said RNA. 33. The method of claim 32 wherein said enzymatic nucleic acid molecule is in a hammerhead motif. 34. The method of claim 32 wherein said enzymatic nucleic acid molecule comprises between 12 and 100 bases complementary to the RNA of fit-I gene. 35. The method of claim 34 wherein said enzymatic nucleic acid molecule comprises between 14 and 24 bases complementary to the RNA of the fit-i gene. 36. A method of treatment of a patient having a condition associated with the level of fit-i, wherein the patient, tissue donor or population of corresponding cells is administered with therapeutically effective amount of a nucleic acid molecule of any one of claims 1 to 9 or an expression vector of claim 37. The use of a nucleic acid molecule of any one of claims 1 to 9 or an expression vector of claim 20 in the manufacture of a medicament for the treatment of a patient having a condition associated with the level of fit-i. 38. A nucleic acid molecule according to any one of claims 1 to 9 or an expression vector of claim 20 when used in the treatment of a patient having a condition associated with the level of fit-i. 39. The method of claim 36, the use of claim 37 or the nucleic acid molecule according to claim 38 wherein said patient is a human. 200 A nucleic acid molecule which modulates synthesis, expression and/or stability of an mRNA encoding fit-1 receptor of vascular endothelial growth factor substantially as hereinbefore described with reference to any one of the Examples. 41. An enzymatic nucleic acid molecule consisting essentially of any ribozyme sequence selected from those shown in Tables II to IX substantially as hereinbefore described with reference to any one of Examples 1 to 7, 9 to 11. Dated 11 September, 2000 Ribozyme Pharmaceuticals, Incorporated Chiron Corporation S S 10 Patent Attorneys for the Applicants/Nominated Persons SPRUSON FERGUSON 60 0 O50 0 °O