AU769175B2 - 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

Name and Address of Applicants: 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 Actual Inventor(s): Address for Service: Invention Title: 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 The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c V DESCRIPTION Method and Reagent for the Treatment of Diseases or Conditions Related to Levels of Vascular Endothelial Growth Factor Receptor Background Of The Invention This invention relates to methods and reagents for the treatment of diseases or conditions relating to the levels of expression of vascular endothelial growth factor S• (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 125 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 cells, receptors of 150 and the 130 kDa have been identified. The VEGF receptors belong to the superfamily of receptor tyrosine kinases (RTKs) characterized by a conserved cytoplasmic catalytic kinase domain and a 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: 1) Tumor anqioqenesis: 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 vascular- S: ization induced by human glioblastoma cells in nude mice S: (Millauer et al., 1994, Nature 367, 576).

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

ed. 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, S. 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.

SDuring 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-i 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 occurring or recombinantly-engineered soluble forms of VEGF receptors to inhibit VEGF activity.

Robinson, International PCT Publication No. WO 95/04142 describes the use of to 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 is 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).

Herein disclosed is use of one or more of the nucleic acid-based techniques to inhibit the expression of fit-1 and/or flk-1/KDR receptors.

According to one embodiment of the invention, there is provided an isolated 25 enzymatic nucleic acid molecule which specifically cleaves fit-1 RNA at site 4229.

According to another embodiment of the invention, there is provided an expression vector comprising a nucleic acid sequence encoding the enzymatic nucleic acid molecule of the invention in a manner which allows expression or delivery of said nucleic acid molecule within a mammalian cell.

According to another embodiment of the invention, there is provided a mammalian cell comprising the enzymatic nucleic acid molecule of the invention, wherein said mammalian cell is not a living human.

According to another embodiment of the invention, there is provided a mammalian cell comprising the expression vector of the invention, wherein said mammalian cell is 35 not a living human. 35 ntalvighmn oo** A02409 According to another embodiment of the invention, there is provided a composition comprising the enzymatic nucleic acid molecule of the invention and a pharmaceutically acceptable carrier.

According to another embodiment of the invention, there is provided a composition comprising the expression vector of the invention and a pharmaceutically acceptable carrier.

According to another embodiment of the invention, there is provided a method of cleaving RNA of the fit-i gene comprising the step of contacting said RNA with the enzymatic nucleic acid molecule of the invention, under conditions suitable for the cleavage of said RNA.

According to another embodiment of the invention, there is provided a method for the treatment of a patient having a condition associated with the level of fit-i, wherein the patient, a tissue donor or population of corresponding cells is administered with a therapeutically effective amount of an enzymatic nucleic acid molecule of the invention, or a composition comprising said enzymatic nucleic acid molecule.

According to another embodiment of the invention, there is provided the use of an enzymatic nucleic acid molecule of the invention, or a composition comprising said enzymatic nucleic acid molecule for the manufacture of a medicament for the treatment of a patient having a condition associated with the level of fit-i.

According to another embodiment of the invention, there is provided a method for the treatment of a patient having a condition associated with the level of fit-i, wherein the patient, a tissue donor or population of corresponding cells is administered with a therapeutically effective amount of an expression vector of the invention, or a composition comprising said expression vector.

25 According to another embodiment of the invention, there is provided the use of an expression vector of the invention, or a composition comprising said expression vector for the manufacture of a medicament for the treatment of a patient having a condition associated with the level of fit-i.

According to another embodiment of the invention, there is provided a method for inhibiting VEGF-mediated induction of endothelial cell proliferation, said method comprising contacting endothelial cells with an enzymatic nucleic acid molecule of the invention, or a composition comprising said enzymatic nucleic acid molecule.

According to another embodiment of the invention, there is provided the use of an enzymatic nucleic acid molecule of the invention, or a composition comprising said 35 enzymatic nucleic acid molecule for the manufacture of a medicament for inhibiting VEGF-mediated induction of endothelial cell proliferation in a patient in need thereof.

A02409 According to another embodiment of the invention, there is provided a method for inhibiting VEGF-mediated induction of endothelial cell proliferation, said method comprising contacting endothelial cells with an expression vector of the invention, or a composition comprising said expression vector.

According to another embodiment of the invention, there is provided the use of an expression vector of the invention, or a composition comprising said expression vector for the manufacture of a medicament for inhibiting VEGF-mediated induction of endothelial cell proliferation in a patient in need thereof.

According to another embodiment of the invention, there is provided a method for io inhibiting VEGF binding to its receptor, said method comprising inhibiting expression of said receptor by cleaving RNA of the fit-i gene with an enzymatic nucleic acid molecule of the invention.

According to another embodiment of the invention, there is provided the use of an enzymatic nucleic acid molecule of the invention, or a composition comprising said enzymatic nucleic acid molecule for the manufacture of a medicament for inhibiting VEGF binding to its receptor in a patient in need thereof.

According to another embodiment of the invention, there is provided the use of an expression vector of the invention, or a composition comprising said expression vector for the manufacture of a medicament for inhibiting VEGF binding to its receptor in a patient in need thereof According to another embodiment of the invention, there is provided a method for inhibiting angiogenesis in a patient in need thereof, said method comprising administering to said patient an enzymatic nucleic acid molecule of the invention, or a composition comprising said enzymatic nucleic acid molecule.

25 According to another embodiment of the invention, there is provided the use of an enzymatic nucleic acid molecule of the invention, or a composition comprising said enzymatic nucleic acid molecule for the manufacture of a medicament for inhibiting angiogenesis in a patient in need thereof.

According to another embodiment of the invention, there is provided the use of an S 30 expression vector of the invention, or a composition comprising said expression vector for the manufacture of a medicament for inhibiting angiogenesis in a patient in need thereof.

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 go• A02409 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 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 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 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-i 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, 20 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 W093/23569, and Sullivan et al., PCT W094/02595, both hereby incorporated in their totality by reference herein; Ohkawa et al., 1992 Nucleic Acids Symp.

Ser., 27, 15-6; Taira et al., 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al., 1993 Nucleic Acids Res., 21, 3249-55; Chowrira et al., 1994 J. Biol. Chem. 269, 25856).

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.

S..By "related" is meant that the reduction of VEGF-R (specifically flt-i 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.

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-i and flk-1/KDR) activity are expressed from transcription units inserted into DNA or RNA vectors. The recombinant 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 i, 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 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 *o 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 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.

W 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 cells. 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'-NH2 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 W 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-i 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; 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-i RNA.

Figure 12 shows inhibition of human microvascular 20 endothelial cell proliferation mediated by anti-flt-1 hammerhead ribozymes. A) Diagrammatic representation of hammerhead (HH) ribozymes targeted against sites 1358 and 4229 within the the flt-1 RNA. B) Graphical representa- .tion 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 lW 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 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-1 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).

W 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-i 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-i 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 V 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 rW 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 Amol 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 gmol) 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 O 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 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 SC 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 TEA*HF/NMP solution (250 pL of a solution of 1.5mL N-methylpyrrolidinone, 750 AL TEA and mL TEA.3HF 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 Al 4 (numbering from q 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, S 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.

Optimizing 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- Wthecal 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 prokarye.e o tic 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., 20 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).

WIn a preferred embodiment of the invention, a transcription unit expressing a ribozyme that cleaves RNAs that encode flt-1, KDR and/or flk-1 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 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 ribozymes in mammalian cells (Ojwang et al., 1992 supra; Thompson et al., 1995 supra).

flt- 1 KDR and/or flk-1 are attractive nucleic e 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 animal models. Finally, the disease conditions are o serious 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 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 Sribozyme 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 o*oo* 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 "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 ribozvmes 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 W 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 0 direct quantitation of surface flt-1, KDR and/or flk-1 on "o 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).

12SI 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 W 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 1X 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: o Percent Inhibition cpm 12 5 I VEGF bound by the ribozyme-treated samples x 100 cpm 1251 VEGF bound by the Control sample Example 3: Effect of hammerhead ribozvmes targeted against flt-1 receptor on the binding of VEGF Hammerhead ribozymes targeted to twenty sites within flt-1 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-1 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 plasmino- W 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-i 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 ribozvmes 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 ribo- 0 zymes 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- W 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).

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

S 15 For anti-flt-1 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 ooo 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 IX 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.

SAs 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-1 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 20 ribozymes targeted against either flt-1 or KDR mRNA can specifically inhibit VEGF-mediated induction of endothelial cell proliferation.

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 W minutes. The gelatin is removed by aspiration and the wells are washed with PBS:Ca 2 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 3 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 mi/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 20 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 33 O 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- 3 p] ATP and 10 T4 polynucleotide kinase (US Biochemicals). Cleavage .reactions were carried out under ribozyme "excess" c.onditions. 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 15 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 e was initiated by mixing the ribozyme and substrate solu- **.tions and incubating at 37"C. Aliquots of 5 ml are taken at regular intervals of time and the reaction is quenched 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 ribozvmes 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.

W 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-1 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-i 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 oo* Since both flt-1 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-i 4229 KDR 527, flt-i 4229 KDR 726 or flt-i 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 g with ribozymes targeted against both flt-i and KDR RNAsflt-i 4229 KDR 527; flt-i 4229 KDR 726; flt-1 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 S* 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 or Millipore® filter disk model, ribozymes are administered within the matrix of the Matrigel or Millipore® filter disk to test their anti-angiogenic efficacy. Thus, delivery issues in this model, as with delivery of ribozymes by Hydron-coated Teflon pellets in the rat 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 U 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.

S* 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 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: Ribozvme-mediated inhibition of anqiogenesis 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-i subtype. The active ribozymes, that are able to bind and cleave the target RNA, have been shown to inhibit 125 -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 Sdose-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-1 4229 (786 pM)- Active b. flt-1 4229 (736 iM)- Inactive S* 2. Experimantal solutions/groups: Group 1 Solution 1 Control VEGF solution: 30 pM in 82mM Tris base Group 2 Solution 2 flt-1 4229 (1 pg/IL) in 30 pM VEGF/82 mM Tris base Group 3 Solution 3 flt-1 4229 (10 pg/pL) in 30 pM VEGF/82 mM Tris base Group 4 Solution 4 No VEGF, flt-1 4229 (10 pg/pL) 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 41 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 AM) was prepared from a stock of 0.82 yg/L in 50 mM Tris base. 200 ML of VEGF stock was concentrated by speed vac to a final volume of 60.8 pL, for a final concentration of 2.7 ig/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.

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 [L 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 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 W 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 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 O 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.

W 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 i. n origin.

Hammerhead Ribozyme 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 RN~A as the infectious agent (Figure 3).

Hepatitis Delta Virus (HDV) Ribozvme 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 Ribozyme Size: -144 nucleotides (at present) Cleavage of target RNAs recently demonstrated.

Sequence requirements not fully determined.

Binding sites and structural requirements not fully determined. Only 1 known member of this class. Found in Neurospora VS RNA (Figure Table II: Human fl tl and Substrate Seouence VEGF Receptor-Hammerhead Ribozvme 20 nt.

Position 13 15 23 43 54 62 97 98 HH Ribozyme Substrate

GCCGAGAG

GGAGCCGA

GAGGAGC C

CCGGGGAG

CUGCCGGG

CCCGcucc

GAGCCCCG

CUGCACCC

CCCCGGGU

UCCCCGGG

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X GAA AGUGUCCG GAA AGGAGUGU GAA AGAGGAGU GAA AGCCGAGA GAA AGGAGCCG GAA AGCCGCCG GAA AGCCCGCU GAA AGCCCCGG GAA AUCCUCGC GAA AAUCCUCG

CGGACACUC

ACACUCCUC

ACUCCUCUC

UCUCGGCUC

CGGCUCCUC

CGGCGGCUC

AGCGGGCUC

CCGGGGCUC

GCGAGGAUUT

CGAGGALTIJA

CUCUCGGC

UCGGCUCC

GGCUCCUC

CUCCCCGG

CCCGGCAG

GGAGCGGG

CGGGGCUC

GGGUGCAG

ACCCGGGG

CCCGGGGA

113 CAGGAGAC CUGAUGA X GAA ACCACUEJC GAAGUGGUU

GUCUCCUG

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

AGCCAGG,

CCAGCCAi CGCGCCC1

GGCCGCC

CGGCCAA(

CCCCGGCC

GUGAGCGC

ACCAUGGI

CAGUAGCt

UGUCCCAC

CACAGCAC

AGACAGCL

GAGAAGCA

CCUGUGAG

UCCUGUGA

GAUCCUGU

CUGAACUA

ACCUGAAC

UGAACCUG

UUGAACCU

UAAUUUJUG

UUAAUULU

GAUCUUUU

GGAUCUUU

CAGUTUCAG

GCCUUUUA

UGCCUUUU

GUGCCUUJ

GCUTUGCAU

GCALUUGGA

CUGCALUUG

A CUGAUGA 3 CUGAUGA LU CUGAUGA

~CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

I CUGAUGA J CUGAUGA

;CUGAUGA

;CUGAUGA

rCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA I

CUGAUGA

CUGAUTGA

CUGAUGA 2

CUGAUGA

CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X X GAA ACAACCAC X GAA AGACAACC K GAA AGCGCCCG K GAA AGUCCGUC (GAA ACCCGGCC C GAA ACGACCCG C GAA ACGCGGCC I 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 AUULUGAA GAA AAUUUUGA GAA AUCUtJUUA GAA ACUCAGUU GAA AACUCAGU GAA AAACUCAG GAA AUGUGCUG GAA AUG CAGUG GAA AGAUGCAG

GUGGLTUGU

GGUUGUCU

CGGGCGCU

GACGGACU

GGCCGGGU,

CGGGUCGUI

GGCCGCGU

GUCGCGCU(

ACCAUGGU(

GGUCAGCU)z

ACCGGGGU(

GCGCUGCUC

UCAGCUGUC

UGUCUGCUL

GUCUGCUJC

CUGCUUCUC

CACAGGAUC

CAGGAUCUA

GAUCUAGUU

AUCUAGUUTC

GUUCAGGUU

UUCAGGUUC

UUCAAAAUU

UCAAAAUTUA

UAAAAGAUC

AACUGAGUJ

ACUGAGUUU

CUGAGUUJUA

CAGCACAUC

CACUGCAUC

CUGCAUCUC

'C UCCUGGCU C CUGGCUGG C AGGGCGCG C UGGCGGCC C GUUGGCCG J3 GGCCGGGG 2GCGCUCAC

ACCAUGGU

AGCUACUG

kCUGGGACA

CUGCUGUG

AGCUGUCU

UGCUUCUC

CUCACAGG

UCACAGGA

ACAGGAUC

UAGUUCAG

GUULCAGGU

CAGGUUCA

AGGUUCAA

CAAAAUUA

AAAAUUAA

AAAAGAUC

AAAGAUCC

CUGAACUG

UAAAAGGC

AAAAGGCA

AAAGGCAC

AUG CAAGC

UCCAAUGC

CAAUGCAG

427 AGACCAtJU CUGAUGA X GAA AUGGGCUG CGCAAAUGC CAGCCCAUA AAUGGUCU 434 CAGGCAAA CUGAUGA X Gk 0 000.00 0* 0000 00 0 0 *000 00 0 00t 0 0 0* *0 0 0009 0 0*00 0**000 *0000.

0 436 437 454 477 481 485 512 513 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

TJUCAGGC

ULUUCAGG

GCUUUCCI

GAIJUUAGI

GGCAGAU1I

CACAGGCJ

UACUGCAC

GUACUGCI

GGUUAAAC

CAAGGU

UCAAGGIJL

UTUCAAGGTJ

CUGUGUUC

GLUJUGCIU

AGCUGUAG

CAGCUGUA

UGCAGCUG

CAGCUAGA

UACAGCUA

GGUACAGC

GAAGUAGG

CUTUUGAAG

CUUCTUUUG

UCUtJCUtJ

AGAUUGCA

AAUAUAUA

UAAAUAJA

AAUAAAUA

CUAAUAAA

CACUAAUA

UCACUAAU

PCUGAUGA

:7 CUGAUGA J CUGAUGA J CUGAUGA J CUGAUGA k~ CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

FCUGAUGA

ICUGAUGA

CUGAUGA

CUGATJGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA)

CUGAUGA

CUGAUGA

CUGAUGA Y~ CUGAUGA 2~ CUGAUGA Y CUGAUGA Y CUGAUGA X KC GA K GAj

GA)J

C GA2 C GA) I GAZ

GA)

GAP

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

~ACCAUUIJA

SAGACCAIU

~AAGACCAU

~ACUCACCA

\AUGCUCAG

SAGUUAUGC

SAUUUAGJU

AUUGUUUG

AAUUGUUU

ACUGCAGA

AGUACUGC

*AAGUACUG

*AAAGUACU

AGGUTUAAA

AGCUGUGU

AGCCAGUG

AAGCCAGU

AGAAGCCA

AIJUUGCAG

AUAUUUGC

AGAUAUUU

ACAGCUAG

AGGUACAG

AGUAGGUA

AAGUAGGU

AUUCUGUU

AUTUGCAGA

AGAIJUGCA

AUAGAUUG

AUAUAGAU

AUAUAUAG

AAUAUAUA

UAAAUGGU,

AAUGGUCU1I

AUGGUCU~LI

UGGUGAGU2

CUGAGCAU)

GCAUAACU)

AACUAAAuC CAAACAAUt

AAACAAUUC

UCUGCAGUP

GCAGUACUU

CAGUACUUU

AGUACUUJUA

UUtJAACCUU)

ACACAGCUC

CACUGGCUU

ACUGGCUEJC

UGGCUUCUA

CUGCAAAUA

GCAAAUAUC

AAAUAUCUA

CUAGCUGUA

CUGUACCUA

UACCUACUU

ACCUACUUC

AACAGAAUC

UCUGCAAUC

UGCAAUCUA

CAAUCUAUA

AUCUAUAUA

CUAUAUALU

UAUAUALUU

C UUUGCCUG J UGCCUGAA J GCCUGAAA

AGGAAAGC

k~ ACUAAAUC k. AAUCUGCC

'UGCCUGUG

JCUGCAGUA

UGCAGUAC

CUUUAACC

UAACCUTUG

AACCUUJGA

ACCUUGAA

GAACACAG

AAGCAAAC

CUACAGCU

UACAGCUG

CAGCUGCA

UCUAGCUG

UAGCUGUA

GCUGUACC

CCUACUUC

CUUCAAAG

CAAAGAAG

AAAGAAGA

UGCAAUCU

UAUAUAUU

UAUAUEJA

UAUTUUAUU

UUUAUUAG

UAULJAGUG

AUUAGUGA

631 AUCACUAA CUGAUGA X GAA AAAUAUAU AAAUAUAUA AUAUAUUUA UuAGuGAU 633 GUAUCACU CUGAUGA X GAA AUAAAUAU AAEtAUAUAA AUAUUUALTU AGUGAUAC 6* 0 0090 .000 0*6 634 640 646 652 653 654 657 665 10 675 684 685 687 711 15 714 717 718 729 730 734 739 744 750 751 754 755 756 764 765 766 771 778 779

UGUAUCAC

UCUACCUC

GAAAGGUC

CUCUACGP

UCUCUACG

AUCUCUAC

UACAUCUC

UUUCACUG

AUUUCGGG

AUGUGUAU

CAtJGUGUA

GUCAUGUG

GGAAUGAC

CAGGGAAU

CGGCAGGG

CCGGCAGG

GGUGACGU

AGGUGACG

UGLUJAGGU

AGUGAUGU

GUAACAGU

UtJUAAAGU UUtUUAAAG

CUUUIJUUA

ACUUUJUUJ

AACUUUUU

CAAGUGGA

UCAAGUGG

GUCAAGUG

AAAGUGUC

AGGGAUCA

CAGGGAUC

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 CUGAUGA GJAA AAUAAAUA GAA AUCACUAA GAA ACCUGUAU GAA AGGUCUAC GAA AAGGUCUA GAA AAAGGUCU GAA ACGAAAGG GAA ACAUCUCU GAA AUUTUCACU GAA AUUTUCGGG GAA AAUUUCGG GAA AUAAUUUC GAA AGCUCCCU GAA ACGAGCUC GAA AUGACGAG

GAA-AAUGACGA

GAA ACCCGGCA GAA AACCCGGC GAA ACGUAACC GAA AGGUGACG GAA AUGUTJAGG GAA ACAGUGAU GAA AACAGUGA GAA AGUAACAG GAA AAGUAACA GAA AAAGUAAC GAA ACUTUULJUU GAA AACUUUtJUU GAA AAACUIUU GAA AGUGGAAA GAA AGUGUCAA GAA AAGUGUCA UAUtJUAUUW

UTUAGUGAUI

AUACAGGU~z

GUAGACCUL

UAGACCUUt

AGACCUUJC

CCLTJUCGUP

AGAGAUGUA

AGUGAAAUC

CCCGAAAUU

CCGAAAUTUA

GAAAUUAUA

AGGGAGCUC

GAGCUCGUC

CUCGUCAUU

UCGUCAUUC

UGCCGGGUU

GCCGGGtJUA

GGUUACGUC

CGUCACCUA

CCUAACAUC

AUCACUGUU

UCACUGUJA

CUGJUACUU.

UGUTUACUUJ

GUTUACUUUA

AAAAAAGTU

AAAAAGUUU

AAAAGUUC

UUUCCACUU

TJUGACACUU

UGACACUUU

kGUGAUACA kCAGGUAGA

GACCUIJUC

TUCGUAGAG

rCGUAGAGA

GUAGAGAU

.GAGAUGUA

CAGUGAAA

CCCGAAAU

AUACACAU

UACACAUG

CACAUGAC

GUCAUUCC

AUUCCCUG

CCCUGCCG

CCUGCCGG

ACGUCACC

CGUCACCU

ACCUAACA

ACAUCACU

ACUGUUTAC

ACUULUAAA

CUUUAAAA

UAAAAAAG

AAAAAAGU

AAAAAGLU

UCCACULYG

CCACUUGA

CACUUTGAC

GACACUUUT

UGAUCCCU

GAUCCCUG

783 801 804 814 824 825 828 831 833 10 845 855 861 862 882 892 893 896 898 908 910 912 919 931 936 939 945 951 969 974 975 978 979 988

CCAUCAGC

UCCCAGAL

CUGUCCCP

GCCCUUUC

AUAUGAUCG

GAUAUGAUJ

UUUGATJAU

GCAUUUGA

UUGCAUEU

UUUCUTUUG

AGAAGCCC

CAGGUCAG

ACAGGUCA

UGCCCAUU

CUUAUACA

UCUtAUAC

UTUGUCUUA

GUTJUGUCU

GUGUGAGA

AUGUGUGA

CGAUGUGU

GGUUUGUC

UAUGALTUG

ACAUCUAU

UGGACAUC

CUTUAUTUUG

GGUGUGCU

AGUAAULUJ

CUCUAAGU

CCUCUAAG

UGGCCUCU

AUGGCCUC

GACAAGAG

;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:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I 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

GAS'

GA7

GA.P

GAP

GAP

GAA

AUCAAAGU

AUGCGUUU

AUUAUGCG

ACUGUCCC

AGCCCUUU

AAGCCCUTJ

AUGAAGCC

*AUGAUGAA

*AUAUGAUG

*ACGtJUGCA

AUUUCLUU

AGCCCUAU

AAGCCCUA

ACUGUUtGC

AUGCCCAU

AAUGCCCA

ACAAAUGC

AUACAAAU

AGUUUGUC

AUAGUJUUG

AGAUAGUU

AUGUGUGA

AUUTGGUUU

AUJUGUALU

AUGAUJGU

ACAUCUAU

AUtJUGGAC

ACUGGGCG

AUUUGACU

AAI~tJUGAC

AGUAAUUU

AAGUAAtU AUGGCCtJC

ACUUUGAUC

AAACGCAUP

CGCAUAAUC

GGGACAGUA

AAAGGGCUU

AAGGGCUUC

GGCUUCAuc

UEJCAUCAUA

CAUCAUAUC

UGCAACGUA

AAAGAAAUA

AUAGGGCUU

UAGGGCUTUC

GCAACAGUC

AUGGGCALU

UGGGCAIUTJ

GCAUUUGUA

AUUEJUGUAUA

GACAAACUA

CAAACUAUC

AACUAUCUC

UCACACAUC

AAACCAAUA

AAUACAAUC

ACAAUCAUA

AUAGAUGUC

GUCCAAAUA

CGCCCAGUC

AGUCAAAUU

GUCAAAUUA

AAAUUACUJ

AAUUACUUA

GAGGCCAUA

CCUGAUGG

LAUCUGGGA

UGGGACAG

*GAAAGGGC

*CAUCAUAU

AUCALAUC

AUAUCAAA

UCAAAUGC

AAAUGCAA

CAAAGAAA

GGGCUTUCU

CUGACCUG

UGACCUGU

AAUGGGCA

UGUAUAAG

GUAUAAGA

UAAGACAA

AGACAAAC

UCUCACAC

UCACACAU

ACACAUCG

GACAAACC

CAAUCAUA

AUAGAUGU

GAUGUCCA

CAAAtJAAG

AGCACACC

AAAUTUACU

ACUUAGAG

CUUAGAGG

AGAGGCCA

GAGGCCAU

CUCUUGUC

991 993 996 999 1003 1006 1012 1018 1022 1035 1036 1051 1052 1069 1078 1079 1083 1095 1108 1109 1122 1124 1125 1127 1134 1135 1137 1138 1141 1143 1173 1174 1175

GAGGACA.

UUtGAGGAi

CAAUUGA(

GUACAAL71

AGCAGUA(

GGtJAGCA(

GGGAGUGC

GUtJCAAGC

UCGUGUUC

GUCAUULUC

GGUCAUL~

AUCAGGGIC

CAUCAGGG

AGCUCUCU

CCUUACGG

GCCUUACG

CGUCGCCU

CUJUUGGUC

GGCAUGGG

UGGCAUGG

CUGUAGAA

CACUGUAG

ACACUGUA

GAACACUG

AUAGUAAG

AAUAGUAA

UCAAUAGU

GUCAAUAG

IJUUGUCAA

AUUUUJGUC

CAAGUAUA

ACAAGUAU

GACAAGUA

kCUGAUGA

:CUGAUGA

3 CUGAUGA J CUGAUGA

CUGAUGA

3CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

rCUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA

CUGAUGA)

CUGAUGA')

CUGAUGA CUGAUGA CUGAUGA )l CUGAUGA Y~ CUGAUGA Y CUGAUGA Y CUGAUGA X C GAI I GA? C GM?

'GAO

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAZA

GAA

GK~

GAj

G.A)

GA)

~AGUAUGGC

~AGAGUAUG

~ACAAGAGU

'AGGACAAG

A. AUJGAGGA

~ACAAUUGA

SAGCAGUAC

AGUGGUAG

AGGGAGUG

ACUCUCGU

AACUCUCG

*ACUCCAGG

*AACUCCAG

ALTUUIUUJU

AGCUCUCU

AAGCUCUC

ACGGAAGC

AUUCGUCG

AUUGCUUU

AAtJUGCUU

AUGUUGGC

AUAUGUUG

AAUAUGU

AGAAUAUG

ACACUGUA

AACACUGU

AGAACACU

AAGAACAC

AGUAAGAA

AUAGUAAG

AGUCCUUU

AAGUCCUU

AAAGUCCU

GCCAUACU(

CAUACUCLR

ACUCUUGUC

CUtJGUCCUC

UCCUCAAUL

.UCAAUUGUz

GUACUGCUP

CUACCACUC

CACUCCCUJ

ACGAGAGUU)

CGAGAGUUC

CCUGGAGUU

CUGGAGUTUA

AAAAAAAUA

AGAGAGCU

GAGAGCUUC

GCUUCCGUA

CGACGAAUU

AAAGCAAUU

AAGCAAUUC

GCCAACAUA

CAACAUAUUI

AACAUAUUC

CAUAUUCUA

UACAGUGU

ACAGUGUTUC

AGUGUUtCUtJ

GUGUJUCUUA

LTUCUUACUA

CUUtACUAUU

AAAGGACUU

AAGGACUUEJ

AGGACUUJA

UUGUCCUC

J GUCCtJCAA

CUCAAUUG

7AAtJUGUAC

IGUACUGCU

CUGCUACC

CCACUCCC

CCUUGAAC

GAACACGA

CAAAUGAC

AAAUGACC

ACCCUGAU

CCCUGAUG

AGAGAGCU

CCGUAAGG

CGUAAGGC

AGGCGACG

GACCAAAG

CCCAUGCC

CCAUGCCA

UUCUACAG

CUACAGUG

UACAGUGU

CAGUGUUC

CUTUACUAU

UUACUALU

ACUALJUGA

CUATUGAC

UUGACAAA

GACAAAAU

UAUACUTUG

AUACUUGU

UACLUTGUC

1177 ACGACAAG CUGAUGA X GAA AUAAAGUC GCUAACUUG GACUUUAUA CUUGUCGU

S.

*5

S

S

C

SSSSSS

1180 1183 1188 1202 1205 1206 1211 1215 1216 1223 1231 1233 1235 1240 1247 1248 1251 1264 1281 1290 1304 1306 1307 1314 1316 1318 1334 1335 1336 1340 1350

UACACGA(

CCUUACA(

CCACUCCI

AUUUGAAT.

CAGAUTUUC

ACAGAUUL

UGUUAAC;

GAGGUGUL

UGAGGUGL

UAUGCACL

AUCAUAUA

UTUAUCAUA

CUTUUAUCA

GAAUGCUU

CAGUGAUG

ACAGUGAU

UUCACAGU

CUGUUUIJC

ACGGUTUUC

UUGCCAGC

GCCGGUAA

GAGCCGGU

AGAGCCGG

UIJCAUAGA

CUTUUCAUA

CACUTUUCA

GCGAGGGA

GGCGAGGG

CGGCGAGG

CUtJCCGGC

AACCAUAC

CUGAUGA

CUGAUGA

J CUGAUGA J CUGAUGA

'CUGAUGA

J CUGAUGA

LCUGAUGA

J CUGAUGA r CUGAUGA

ICUGAUGA

*CUGAUGA

*CUGAUGA

*CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA I CUGAUGA CUGAUGA CUGAUGA 'GAA AGUAUAAA :GAA ACAAGUAU :GAA ACACGACA GAA AUGGUCCA GAA AUGAUGGU GAA AAUGAUGG GAA AUUUGAAU GAA ACAGAUJU GAA AACAGAUEJ GAA AGGUGUUA GAA AtJGCACUG GAA AUAUGCAC GAA AUAUAUGC GAA AUCAUAUA GAA AUGCUUUA GAA AAUGCUU GAA AUGAAUGC GAA AUGUTJLCA GAA ACCACCUG GAA ACGGUUUC GAA ACCGCUUJG GAA AGACCGCU GAA AAGACCGC GAA AGCCGGUA GAA AGAGCCGG GAA AGAGAGCC GAA AUG CCUUC GAA AAUGCCUU GAA AAAUGCCU GAA AGGGAAAU GAA ACUUCCGG

UUUAUACLT[

AUACUUTGUC

UGUCGUGUI

UGGACCAUC

ACCAUCAUL

CCAUCAUUC

AUUCAAA.UC

AAAUCUGUL

AAUCUGUUP

UAACACCUC

CAGUGCAUA

GUGCAUAUA

GCAUAUAUA

UAUAUGAUA

UAAAGCAUJ

AAAGCAUTUC

GCAUTUCAUC

UGAAACAUC

CAGGUGCUtJ

GAAACCGUA

CAAGCGGUC

AGCGGUCUU

GCGGUCUUA

UACCGGCUC

CCGGCUCUC

GGCUCUCUA

GAAGGCAU

AAGGCAUJU

AGGCAUUUC

AUUUCCCUC

CCGGAAGUU

J GUCGUGUA

-GUGUAAGG

k. AGGAGUGG

.AUUCAAU

J CAAAUCUG AAAUCtJGU UGUtJAACA

FAACACCUC

ACACCUCA

AGUGCAUA

UAUAUGAU

UAUGAUAA

UGAUAAAG

AAGCAUTUC

CAUCACUG

AUCACUGU

ACUGUGAA

GAAAACAG

GAAACCGU

GCUGGCAA

UUACCGGC

ACCGGCUC

CCGGCUCU

UCUAUGAA

UAUGAAAG

UGAAAGUG

UCCCUCGC

CCCUCGCC

CCUCGCCG

GCCGGAAG

GUAUGGU

1353 UTUUAACCA CUGAUGA X GAA ACAACUUC GAUGAUGUA GAAGUUGUA UGGUUAAA 1358 CAUCtUUUU CUGAIJGA X G.AA ACCAUACA UUUGUAAGU UGUAUGGUU

AAAAGAUG

135S 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 PCCAUCUL71

UCGCAGGT

GUCGCAG(

AGCGAGC3

CAAAUAGC

GAGUCAA;

ACGAGUCP

CACGAGUC

GUAGCCAC

UTUAACGAG

UAATJUAAC

UGAUAAUU

UUGAUAAU

UCCUUGAU

GUCCUTUGA

ACGUCCUJ

UCUUCAGU

GALUUAU

AGAUUGUA

CAAGAUUG

CUCAGCAA

UGCUCAGC

GACUGLTUU

ACACAULU

GGUUULUA

AGGUUUUU

GAGGUEUU

GUGGCAGU

GACAAUUA

UUGACAAU

ACAUUGAC

J CUGAUGA J CUGAUGA

;CUGAUGA

SCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA

CUGAUGA)

CUGAUGA 2 CUGAUGA 2

CUGAUGA

CUGAUGA Y C~ GAA AACCAUAC C GAA ACCCAUCU CGAA AACCCAUC 'GAA AUUUCUCA GAA AGCAGAUU GAA AGCGAGCA GAA AUAGCGAG GAA AAUAGCGA GAA AGUCAAAU GAA AGCCACGA GAA AGUAGCCA GAA ACGAGUAG GAA AACGAGUA GAA ALTUAACGA G.AA AAUUIAACG GAA AUAAUUAA GAA ACGUCCUU GAA AUUCCCUG GAA AAUTUCCCU GAA AUAAUUCC GAA AUUTGUAUA GAA AGAUUGUA GAA AUGCUCAG GAA ACUGULUU GAA ACACAUUU GAA AACACAUU GAA AAACACAU GAA AGGUUULU GAA AGUGGCAG GAA AGAGUGGC GAA AUUJAGAGU

GUAUGGUU

AGAUGGGU

GAUGGGUU.

UGAGAAAU

AAUCUGCU

UGCUCGC~j

CUCGCUAU

UCGCUAULTI

AUUJGACU(

UCGUGGCUI

UGGCUACUC

CUACUCGU.

UACUCGUU;

UCGUUAAUT

CGUUAALUP

UUAAUTUAUC

AAGGACGUA

CAGGGAAUU

AGGGAAUUA

GGAAUUAUA

UAUACAAUC

UACAAUCUU

CUGAGCAUA

AAAACAGUC

AAAUGUGUU

AAUGUGUUU

AUGUGUTUUA

AAAAACCUC

CUGCCACUC

GCCACUCUA

ACUCUAAUU

A AAAGAtJGG U ACCUGCGA A~ CCUGCGAC C UGCUCGCU

GCUAULJTJG

k. UUTJGACUC J UGACUCGU J GACUCGUG

-GUGGCUAC

k. CUCGUUAA

GIUAAUUA

JAAUUAUCA

SAUUAUCAA

TAUCAAGGA

LUCAAGGAC

AAGGACGU

ACUGAAGA

AUACAAUC

UACAAUCU

CAAUCUUG

UUGCUGAG

GCUGAGCA

AAACAGUC

AAAUGUGU

UAAAAACC

AAAAACCU

AAAACCtJC

ACUGCCAC

UAAUtJGUC AUtJGUCAA

GUCAAUGU

1521 UUCACAUU CUGAUGA X GAA ACAAUUAG CATtGCAUUA CUAAUUGUC

AAUGUGAA

1539 1540 1541 1556 1559 1562 1563 1564 1576 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 CGGGUCUG CUGAUGA X GAA UGGGUAGA CUGAUGA X GAA AGUGGGUA CUGAUGA X GAA CCAGUGGG CUGAUGA X GAA CAAGUCAG CUGAUGA X GAA UGCGGUAC CUGAUGA X GAA AUAUGCGG CUGAUGA X GAA GGAUACCA CUGAUGA X GAA UTUGAGGGA CUGAUGA X GAA GGUUGAGG CUGAUGA X GAA UGUAGGUU CUGAUGA X GAA CUUGAUTUG CUGAUGA X GAA

AAACGAUG

AGCCGGGU

AGAGCCGG

AGAGAGCC

AUUUGUCU

AGUCAGGA

ACAAGUCA

AUGCGGUA

ACCAUAUG

AUACCAUA

AGGGAUAC

AGGLTUGAG

UUUUCGUA CUGAUGA X GAA AUCUGGGG CUUUUCGU CUGAUGA X GAA AAUCUGGG CCUUUUCG CUGAUGA X GAA AAAUCUGG GAAACGAU CUGAUGA X GAA ACACGGCC CUGGAAAC CUGAUGA X GAA AUGACACG GGUCUGGA CUGAUGA X GAA ACGAUGAC GGGUCUGG CUGAUGA X GAA AACGAUGA CCCCAGAUU UACGAAAA CCCAGAUUU ACGAAAAG CCAGAUUUA CGAAAAGG GGCCGUGUC AUCGUUUC CGUGUCAUC GUUUCCAG GUCAUCGUU UCCAGACC UCAUCGUTUU CCAGACCC CAUCGUTUUC CAGACCCG ACCCGGCUC UCUACCCA CCGGCUCUC UACCCACU GGCUCUCUA CCCACUGG AGACAAAUC CUGACUUG UCCUGACUJ GUACCGCA UGACUUGUA CCGCAUAU UACCGCAUA UGGUAUCC CAUAUGGUA UCCCUCAA UAUGGUAUC CCUCAACC GUAUCCCUC AACCUACA CUCAACCUA CAAUCAAG CCUACAAUC AAGUGGUU CAAGUGGUU CUGGCACC AAGUGGUUC UGGCACCC ACCCCUGUA ACCAUAAU GUAACCAUA AUCATJUCC ACCAUAAUC AUUCCGAA AUAAUCAUU CCGAAGCA UAAUCAUUC CGAAGCAA GUGUGACUU UUGUUCCA UGUGACUUU UGUUCCAA GUGACUUUU GUUCCAAU ACUUULJGUIJ CCAAUAAU CUUUUIGUUC CAAUAAUG GUUCCAAUA AUG.AAGAG .5.55.

AACCACUU CUGAUGA X GAA AUUGUAGG GGUGCCAG CUGAUGA X GAA ACCACUUG GGGUGCCA CUGAUGA X GAA AACCACUU AUUAUGGU CUGAUGA X GAA ACAGGGGU GGAAUGAU CUGAUGA X GAA AUGGUtJAC UTUCGGAAU CUGAUGA X GAA AUUAUGGU UGCUUCGG CUGAUGA X GAA AUGAUUAU UUGCUUCG CUGAUGA X GAA AAUGAUUA UGGAACAA CUGAUGA X GAA AGUCACAC UUGGAACA CUGAUGA X GAA AAGUCACA AUUGGAAC CUGAUGA X GAA AAAGUCAC AUTUAUUTGG CUGAUGA X GAA ACAAAAGU CAUUAUUG CUGAUGA X GAA AACAAAAG CUCUUCAU CUGAUGA X GAA AUUGGAAC 1715 GGAUAAAG CUGAUGA X GAZ 1718 1719 1720 1722 1755 1764 1768 1782 1785 1798 1807 1814 1818 1829 1831 1836 1837 1838 1845 1847 1851 1852 1857 1861 1862 1867 1872 1893 1898 1899 1900 1901 CCAGGAU2

UCCAGGAT

AUCCAGGZ

GCAUCCAC

AUGCUCUC

CGCUGAGt

CAUGCGCL

CCLTUCUAt UutLJCCLTEJc

AGCCAUCL

CAAGGUGC

CCACAACC

UCAGCCAC

AAAUUCUA

AGAAAUIJC

AUUCCAGA

GAUEJCCAG

AGAUTUCCA

CAAAUGUA

UGCAAAUG

GCUAUGCA

AGCUAUGC

UUGGAAGC

UUUAUUGG

CUUUAUUG

CCCAACUU

ACAGUCCC

UAAAAGCU

UGAUAUAA

GUGAUAUA

UGUGAUAU

k. CUGAUGA J CUGAUGA k. CUGAUGA

CUGAUGA

CUGAUGA

JCUGAUGA

TCUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA

CUGAUGA)

CUGAUGA

CUGAUGA CUGAUGA Y~ CUGAUGA Y~ CUGAUGA Y KGA7

SGAP~

CGAP

C GAP~ I GA-A

'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

ACUCUIJCA

AGGACUCU

AAGGACUC

AAAGGACU

AUAAAGGA

ALUJCUGUU

AUGCUCUC

AGUGAUGC

ALUJGCCAU

ATEJALUGC

AUTUCLJUUC

AGCCAUCU

AGGUGCUA

ACCAAGGU

AGUCAGCC

AGAGUCAG

AUUCUAGA

AALUIJCUAG

AA.AUUCUA

AUJUCCAGA

AGALUJCCA

AUGUAGAU

AAUGUAGA

AUGCAAAU

AGCUAUGC

AAGCUAUG

AUTUGGAAG

ACUtJUJAUU

AUGUTUUCU

AGCUUAUG

AAGCUTUAU

AAAGCLTUA

UGAAGAGU(

AGAGUCCMt

GAGUCCUUL

AGUCCJIJW

UCCUUUAUC

AACAGAAUL

GAGAGCAUC

GCAUCACUC

AUGGCAAUA

GCAAUAAUA

GAAAGAAUA

AGAUGGCUA

UAGCACCUU

ACCUUGGUU

GGCUGACUC

CUGACUCUA

UCUAGAAUU

CUAGAAUU

UAGAALTUUC

UCUGGAAUC

UGGAAUCUA

AUCUACALU

UCUACAUU

AULUJGCAUA

GCAUAGCUU

CAULAGCUUC

CUUCCAAUA

AAUAAAGUU

AGAAACAUA

CAUAAGCUU

AUAAGCUUU

UAAGCUUUUJ

-CUUIJAUCC

J UAUCCUGG J AUCCUGGA

UCCUGGAU

CUGGAUGC

GAGAGCAU

ACUCAGCG

AGCGCAUG

AUAGAAGG

GAAGGAAA

AGAUGGCU

GCACCUTUG

GGUUGUGG

GUGGCUGA

UAGAALUU

GAAUUUCU

UCUGGAAU

CUGGAAUC

UGGAAUCU

UACAtJUUG

CAUTUUGCA

UGCAUAGC

GCAUAGCU

GCUYUCCAA

CCAAUAAA

CAAUAAAG

AAGUTUGGG

GGGACUGU

AGCUUUIJA

UUAUAUCA

UAUAUCAC

AUAUCACA

CUGUGAUA CUGAUGA X GAA AAAAGCUU AGUUU

AUAA

AAGCUUUUA UAUCACAG 1903 1905 1925 1926 1927 1932 1933 1937 1976 10 1978 1986 1987 1994 1995 1997 1998 2000 2010 2011 2014 2019 2020 2021 2022 2034 2035 2038 2054 2059 2061 2062 2082 2086

AUCUGUGP

ACAUCUGtJ

UAACAUGA

UUAACAUG

GUUtAACAU UCCAAGtU

LUCCAAGU

UUUUUUcc

CUGUGCAA

AACtJGUGC

AACUUGUU

GAACUTUGU

UGUAUAAG

CUGUAUAA

CUCUGUAU

UCUCUGUA

CGUCUCUG

AUCCAAGU

AAUCCAAG

UAAAAUCC

CGCAGUAA

CCGCAGUA

UCCGCAGU

GUCCGCAG

CUGUJAU

UCUGUAU

UGUUCUGU

UAAUACUG

CUUGCUAA

UGCUUGCU

LTUGCUUGC

UCCUUIAGU

GUGCUCCU

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

GAA

GAA

GAA

GAA

GAA

GAA

AUAAAAGC

AUAUAAAA

ACCCAULU

AACCCAUU

AAACCCAU

ACAUGAAA

AACAUGAA

AGUUAACA

ACAGUUTUC

AGACAGUU

ACUGUGCA

AACUGUGC

ACUUGUTUA

AACUUGUU1

AGAACUUIG

AAGAACUU

AUAAGAAC

ACGUCUCU

AACGUCUC

AGUAACGU

AUCCAAGU

AAUCCAAG

AAAUCCAA

AAAAUCCA

ACUGUCCG

AACUGUCC

AUTUAACUG

AGUGCAUUJ

ACUGUAGU

AUACUGUA

AAUACUGU

AUGGCCAU

AGUGAUGG

GCUUUUAUA

UUUTUAUAUC

AAAUGGGLU

AAUGGGUUU

AUGGGUTUUC

UTJUCAUGU

UTUCAUGULJA

UGUUAACUUT

GAAACUGUC

AACUGUCUU

UGCACAGUUT

GCACAGUTUA

UAACAAGUU

AACAAGUTUC

CAAGUTUCLU

AAGUUCUTUA

GUUCUUAUA

AGAGACGLU

GAGACGUTUA

ACGUULACTU

ACUUGGALU

CUUGGAUUU

tJUGGAUUUU UGGAtUUUA

CGGACAGUU

GGACAGUUA

CAGUUAAUA

AAUGCACUA

ACUACAGUA

UACAGUAUUJ

ACAGUAUTUA

AUGGCCAUC

CCAUCACUA

UCACAGAU

ACAGAUGU

UCAUGUUA

CAUGUUJAA

AUGtJUAAC

AACUUGGA

ACUUGGAA

GGAAAAAA

UUGCACAG

GCACAGUU

AACAAGUU

ACAAGUTLJC

CUUAUACA

UTUAUACAG

AUACAGAG

UACAGAGA

CAGAGACG

ACUUJGGAU

CLTUGGAUU

GGAUUUTUA

UUACUGCG

UACUGCGG

.ACUGCGGA

CUGCGGAC

AAUAACAG

AUAACAGA

ACAGAACA

CAGUAUUA

LTUAGCAAG

AGCAAGCA

GCAAGCAA

ACUAAGGA

AGGAGCAC

A*

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

UUtAAGAGI AAGAUUAj

GUAAGAUI

GGUAAGAT

GAUGGUAZ

ALJGAUGGI

CAUGAUGC

ACAUUCAJ

UGCAGGGA

UUGCAGGG-

CUUGCAGG

GGUGCCUG

AGGUGCCU

UGCAGGCA

CCUGUGUA

CCCCUGUG

UTUCUGGAG

UUCUUCUG

CUGAUTUGU

UCUGAUUG

UGAUCUCU

UGCUIJCCU

GCAGGAGG

UUUCGCAG

UGAUCACU

CACUGUGU

GAACUGCU

AGUGGUGG

AAGUGGUG

ACAGUCUA

GACAGUCU

UJGACAGUC

3 CUGAUGA J CUGAUGA

CUGAUGA

J CUGAUGA

JCUGAUGA

CUGAUGA

J CUGAUGA

;CUGAUGA

TCUGAUGA

CUGAUGA

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 K GAA AGUGCUCC K GAA AUGGAGUG SGAA AGUGAUGG C GAA AGAGUGAU C GAA AAGAGUGA IGAA AUUAAGAG GAA AGAUUAAG GAA AAGAtJUAA GAA AUGGUAAG GAA ACAUUCAU GAA AACAUUCA GAA AAACAUUC GAA AUCUUGCA GAA AAUCUUGC GAA AGGUGCCU GAA ACAUUCCU GAA AUACAUTUC GAA AUUUCUIFJC GAA AGGAUUUC GAA AUtJUCUUU GAA AAUUUCUU GAA AUUGUAAU GAA AUCUCUGA GAA AUGGUGCU GAA AGGUAUGG GAA AGGUUUCG GAA AUCACUGA GAA AUGGCCAC GAA ACUGCUGA GAA AACUGCUG GAA AGUGGUGG GAA AAGUGGUG GAA AAAGUGGU

GGAGCACUC

CACUCCAUC

CCAUCACUC

AUCACUCUU

UCACUCUUA

CUCUUAAUC

CUUAAUCUU

LUUAAUCUTUA

CUUACCAUC

AUGAAUGUU

UGAAUGUUU

GAAUGUUUC

UGCAAGAUU

GCAAGAUUC

AGGCACCUA

AGGAAtJGUA

GAAUGUAUA

GAAGAAAuc

GAAAUCCUC

AAAGAAAUU 2

AAGAAAUUA

AUUACAAUC

UCAGAGAUC

AGCACCAUAC

CCAUACCUC C

CGAAACCUCP

UCAGUGAUC

GUGGCCAUC

UCAGCAGUIJ C CAGCAGUtJCC

CCACCACUUU

CACCACUUU

A

ACCACUUUAG

CAUCACUC

ACUCUUAA

UUAAUCU

AAUCUTUAC

AUCUUACC

UTUACCAUC

ACCAUCAU

CCAUCAUG

AUGAAUGU

UCCCUGCA

CCCUGCAA

CCUGCAAG

CAGGCACC

AGGCACCU

EJGCCUGCA

LJACACAGG

CACAGGGG

CUCCAGAA

:AGAAGAA

kCAAUCAG

:AAUCAGA

k.GAGAUCA

GGAAGCA

CUCCUGC

~UGCGAAA

~GUGAUCA

LCACAGUG

LGCAGLTUC

CACCACU

ACCACU

'AGACUGU

GACUGUC

ACUGUCA

2296 AUUAGCAU CUGAUGA X GAA ACAGUCUA 2302 GACACCAU CUGAUGA X 96 9 9

C

4 9 4* 4 9 2310 2320 2325 2329 2333 2334 2335 10 2352 2370 2371 2373 2374 15 2375 2376 2399 2400 2401 2403 2412 2433 2435 2437 2465 2476 2477 2483 2487 2493 2494 2504 2513

GGCUCGGG

AGUGAUCU

AACCAAGU

UUUAAACC

UGUUUtUUA

UTUGUUUUU

GUTUGULUU

UCUUGUIJG

CCUAAAAU

UCCUAAAA

GGUCCUAA

UGGUCCUA

CUGGUCCU

CCUGGUCC

UUUCAAUA

CUUUJCAAU

UCUTJUCAA

ACUCUUUC

UCUUTCUGU

CAGUGAUA

UGCAGUGA

UUEUGCAGU

UUUCCACA

GUAUGCUG

GGUAUGCU

CAGUGAGG

UGAACAGU

GLTUCCUTUG

GGUUCCUU

ACLUGUCC

CCAGAUTUA(

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 AGCAUGAC GAA ACACCAUU GAA AGGCUCGG GAA AtJCUGAGG GAA AGUGAUCU GAA ACCAAGUG GAA AACCAAGU GAA AAACCAAG GAA AUtTUUGUG GAA AUTUCCAGG GAA AAUUCCAG GAA AUAAUUCC GAA AAUAAUTUC GAA AAAUAALU GAA AAAAUAAU GAA ACAGCGUG GAA AACAGCGU GAA AAACAGCG GAA AUAAACAG GAA ACUCUUTUC GAA ACACCUTUC GAA AGACACCU GAA AUAGACAC GAA AGCCCUUC GAA ACUUUCCA GAA AACUUUCC GAA AUG CUGAA UAGACUGUC

AUGCUAAU

GUCAUGCUA

AUGGUGUC

AAUGGUGUC

CCCGAGCC

CCGAGCCUC

AGAUCACU

CCIJCAGAUC ACUUGGUU AGAUCACUU GGUUUAAA CACIJUGGUU

UAAAAACA

ACUUGGUUU AAAAACAA CUUGGUUUA

AAAACAAC

CACAAAAUA CAACAAGA CCUGGAAUU AUUUUAGG CUGGAALUA UUUUAGGA GGAAUUAUU

UUAGGACC

GAAUUAUUU

UAGGACCA

AAUtJAUUUU

AGGACCAG

ALJTJAUUJUUA GGACCAGG CACGCUGUU UAUUGAAA ACGCUGUTUU AUUGAAAG CGCUGtJUUA UUGAAAGA CUGUUUAUU

GAAAGAGU

GAAAGAGUC

ACAGAAGA

GAAGGUGUC UAUCACUG AGGUGUCUA UCACUGCA GUGUCUAUC ACUGCAAA GAAGGGCUC UGUGGAAA UGGAAAGUU

CAGCAUAC

GGAAAGUtJC

AGCAUACC

UUCAGCAUA

CCUCACUG

GCAUACCUC ACUGUUtCA CUCACUGUTU

CAAGGAAC

UCACUGUUC AAGGA ACC AGGAACCUC

GGACAAGU

GGACAAGUC UAAUCUGG CUGAUGA X GAA AGGUAUGC CUGAUGA X GAA ACAGUGAG 'UGAUGA X GAA AACAGUGA :UGAUGA X GAA AGGUUCCU :UGAUGA X GAA ACUUGUCC 2515 CUCCAGAU CTJGAUGA X GAA AGACUUGU

S.

S

i 555.55 0* 5 4* e *o

S

2518 2529 2533 2535 2560 2562 2564 2565 10 2571 2574 2576 2577 2583 2586 2587 2589 2606 2608.

20 2609 2611 2612 2619 2630 2634 2636 2640 2641 2643C 2661 L 2662 2665 C

CAGCIJCCA

GUUAGAGU

GCAtJGUJA

GUGCAUGU

CCAGAAGA

AGCCAGAA

GGAGCCAG

AGGAGCCA

GUUAAUAG

AGGGUUTAA

GGAGGGUU

AGGAGGGU

CGGAUAAG

UUTUCGGAU

UUUTUCGGA C AUUUUEJCG

C

CAGAAGAA c UIJCAGAAG C UUUCAGAA

C

UAUUUCAGC

UJAIJLTCA

C

UCAGUCtU c IJUGAUAGG Cl DUAAUUGA Cl JTUAUAAUU

C

JCCALTAU

C

3UCCALUA

C

;GGUCCAU Ct JCCAAAGG Ct LUCCAAAG CL ~UCAUCCA cU CTJGAUGA X CUGAUGA X CUGAUGA

X

CUGAUGA x CUGAUGA

X

CUGAUGA X CUGAUGA

X

CUGAUGA x CUGAUGA x CUGAUGA X CUGAUGA X CUGAUGA x ZUGAUGA X 'UGAUGA X ~UGAUGA X ~UGAUGA X UGAUGA X UGAUGA X 'UGAUGA X UGAUGA X UGAUGA XC LGAUGA XC LIGAUGA XC JGAUGA XC JGAUGA X JGAUGA XG JGAUGA XG JGAUGA XG JGAUGA X G TGAUGA X G [GAUGA X G

GI

G;

GIA

G.A

GA

GA

GA

GA

GA

GA

GA

GAj GAj

;AA

;AA

;AA

'AA

'AA

'AA

AA

AA AUUAGACU kA AUCAGCUC %A AGUGAUCA k.A AGAGUGAU

~AGUCGCAG

~AGAGUCGC

LAGAGAGUC

AAAGAGAGU

AAGCCAGAA

AAGGAGCCA

AAUAGGAGC

AAAUAGGAG

PAGGGUUAA

SAGGAGGGU

~AAGGAGGG

~AUAAGGAG

SACCUUtJtJC

SAGACCUUU

AAGACCUU

AGAAGACC

AAGAAGAC

AULUJCAGA

AGUCAGUC

AGGUAGUC

AUAGGUAG

AUUGAUAG

AAUUGAUA

AUJAAUUGA

ACUUCAUC

AACUTJCAU

ACAAGUCUA

AUCUGGAG

AGUCUAAUC

UGGAGCUG

GAGCUGAUC

ACUCUAAC

UGAUCACUC

UAACAUGC

AUCACUCUA

ACAUCCAC

CUGCGACUC

UCUUCUGG

GCGACUCUC tJUCUGGCU GACUCUCUU

CUGGCUCC

ACUCUCUUC

UGGCUCCU

UUCUGGCUC

CUAUUAAC

UGGCUCCUA

UUAACCCU

GCUCCUAUJ

AACCCUCC

CUCCUAUUA

ACCCUCCU

UUAACCCUC

CUUAUCCG

ACCCUCCUU

AUCCGAAA

CCCUCCUUA

UCCGAAAA

CUCCUUAUC

CGAAAAAU

GAAAAGGUC

UUCUUCUG

AAAGGUCUU

CUCUGAA

AAGGUCUUC

UUCUGAAA

GGUCUUCUU

CUGAAAUA

GUCUUCUUC

UGAAAUAA

UCUGAAAUA

AAGACUGA

GACUGACUA

CCUAUCAA

GACUACCUA

UCAAUUAU

CUACCUAUC

AAUUAUAA

CUAUCAAUU

AUAAUGGA

UAUCAAUUA

UAAUGGAC

UCAAUUAUA

AUGGACCC

GAUGAAGUU

CCUUUGGA

AUGAAGUUC

CUUUGGAU

AAGUUCCUUJ

UGGAUGAG

AGUTUCCIJUYU

GGAUGAGC

S

S

0 2666 GCUCAUCC CUGAUGA X GAA AAGGAACU 0 *9 0 0.

9999: 2688 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

UCAUAAGC

GGCAUCAL

UGGCAUC~z

CCCGGGCP

UCCCGGGC

CCCAGUUU

GCCCAGUU

UUCCAAGU

ccUcUUcc

TUUUCCAA

CUtUUCCA

ACUUTUUCC

GAUGCUTUG

UGAUGCUU

CAAAUGCU

UAAUGCCA

UUAAUGCC

GAUUEJCUU

UGAUUTUCU.

ACGUAGGU

CCGGCACG

GAGCLTUUG

AGUCAUCA

AAGAUUU

UGGGUCAA

UGUGGGUC

UGGUGGCC

CACGUUCA

AGCAGGUU

CAGCAGGU

CACCAUCA

UALTUCAAC

CAGUALTUC

'CUGAUGA

JCUGAUGA

LCUGAUGA

LCUGAUGA

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 I CUGAUGA CUGAUGA I CUGAUGA IGAA AGCCGCUC 'GAA AGGGAGCC 'GAA AAGGGAGC GAA ACUCCCAC GAA AACUCCCA GAA AGUCUCUC GAA AAGUCUCU GAA AUUUGCCC GAA AGUGAUUU GAA AGCCCCUC GAA AAGCCCCU GAA AAAGCCCC GAA ACCACUUUJ GAA AACCACLU GAA AUG CUUTGA GAA AUG CUGAU GAA AAUGCUGA GAA AUGCCAAA GAA AAUGCCAA GAA AUUUCUUA GAA AGGUGAUU GAA ACUCGCUG GAA AGCUUUGU GAA AGCUCAGU GAA AUUUUUAG GAA AGAUUUU GAA AUGUGGGU GAA AUGGUGOC GAA ACCACGUU GAA AACCACGU GAA AGGCCCUC GAA AUCACCAU GAA ACAAUCAC

GAGCGGCUC

GGCUCCCUL

GCUCCCULUI

GUGGGAGUL

UGGGAGUUC

GAGAGACUL

AGAGACUUA

GGGCAAAUC

AAAUCACUU

GAGGGGCUJ

AGGGGCUUU

GGGGCUUUU

AAAGUGGUU

AAGUGGUTUC

UCAAGCAUC

AUCAGCAUU

UCAGCAUUU

UUUGGCAUU

UTUGGCAUTUA

UAAGAAAUC

AAUCACCUA

CAGCGAGUA

ACAAAGCUC

ACUGAGCUA

CUAAAAAUC

AAAAAUCUU

ACCCACAUU

GCCACCAUC

AACGUGGUU

ACGUGGUUA

GAGGGCCUC

AUGGUGALU

GUGAUUTGUU

ICCLTUAUGA

JAUGAUGCC

UGAUGCCA

IUGCCCGGG

rGCCCGGGA

IAAACUGGG

AACUGGGC

*ACUUGGAA

GGAAGAGG

UTUGGAAAA

UGGAAAAG

GGAAAAGU

CAAGCAUC

AAGCAUCA

AGCAUUTUG

UGGCAUTUA

GGCAUUTAA

AAGAAAUC

AGAAAUCA

ACCUACGU

CGUGCCGG

CAAAGCUC

UGAUGACU

AAAAUCUU

UUGAC CCA

GACCCACA

GGCCACCA

UGAACGUG

AACCUGCU

ACCUGCUG

UGAUGGUG

GUTUGAAUA

GAAUACUG

2981 AUULJGCAG CUGAUGA X GAA AUUCAACA UUGAACGAA UGUUGAAUA

CUGCAAAU

S.

I

S

S

S

2990 2998 3000 3002 3008 3012 3029 3030 10 3032 3033 3034 3035 3036 15 3037 3039 3057 3070 3120 20 3124 3129 3146 3147 3155 3161 3162 3163 3172 3178 3189 3205 3206

GAUTUUCC

GUUIGGAG

UAGUTUGG

GGUAGUU,

UCUUGAGi

UUGCUCUI

GAAAAAAI

AGAAAAAj UGAGAAA2

UTUGAGAA.'

GUTUGAGAZ

UGLTUGAG;

UTUGLTUGAC

CUtJGLUGP

UCCUUGUL

UCCAUGUG

UUCLUUtCU

ACGCUAUC

GGUGACGC

CUGCUGGU

AGCUCGCA

GAGCUCGC

GAAAGCCG

CUTUCCUGA

UCUUCCUG

AUCUUCCU

CAGACUU

AUCACUCA

ucuucuc

ACCGUCAG

AACCGUCA

A CUGAUGA A CUGAUGA A CUGAUGA 3 CUGAUGA 3; CUGAUGA J CUGAUGA J CUGAUGA

CUGAUGA

CUGAUGA

k CUGAUGA

SCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGATJGA:

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA

CUGAUGA 2 CUGAUGA 2 CIJGAUGA Y' CUGAUGA Y' CUGAUGA Y CUGAUGA X CUGAUGA X X GAA AUUUJTGCAG X GAA AUUTUCCAU K GAA AGAUUUCC K GAA AGAGAULU GAA AGUUGGAG GAA AGGUAGU C GAA AGUCACGU C GAA AAGUCACG GAA AUAAGUCA GAA AAUAAGUC GAA AAAUAAGU GAA AAAAUAAG GAA AAAAAUAA GAA AAAAAAUA GAA AGAAAAAA GAA AGUGCUGC G.AA AGGCUCCA GAA AGUCUTUGG GAA AUCUAGUC GAA ACGCUAUC GAA AGCUUJCG GAA AAGCUUUC GAA AGCUCGCA GAA AGCCGGAG GAA AAGCCGGA GAA AAAGCCGG GAA AUCUUCCU GAA ACtUUUAU GAA ACAUCACU GAA AUCCUCCU GAA AAUCCUCC

CUGCAAAU

AUGGAAAU

GGAAAUCU

AAAUCUCU

CUCCAACU

AACUACCUC

ACGUGACUI1

CGUGACUU)

UGACUJALTI

GACUUAJUL

ACUJAUUUL.

CUUAUtUL UUtAUUtUU

UAUUUUUUC

UUUUUUCUC

GCAGCACUA

UGGAGCCUA

CCAAGACUA

GACUAGAUA

GAUAGCGUC

CGAAAGCUU

GAAAGCUUU

UGCGAGCUC

CUCCGGCUU

UCCGGCUUJ

CCGGCUJUC

AGGAAGAUA

AUAAAAGUC

AGUGAUGUU

AGGAGGAUU

GGAGGAUUC

A UGGAAAUC C UCUCCAAC C UCCAACUjA 2 CAACIJACC rk CCUCAAGA

AAGAGCAA

J AUUUtJUC kUUUTUUUCU

JULUUUCUCA

J UUUCUCAA J UUTCUCAAC

FUCUCAACA

rCUCAACAA

UCAACAAG

AACAAGGA

CACAUGGA

AGAAAGAAi

GAUAGCGU

GCGUCACC

ACCAGCAG

UGCGAGCU

GCGAGCUC

CGGCUJUC

UCAGGAAG

CAGGAAGA

AGGAAGAU

AAAGUCUG

UGAGUGAU

GAGGAAGA

CUGACGGU

UGACGGLU

3214 CUUGUAGA CUGAUGA X GAA ACCGUCAG CUGACGGUU UCUACAAG K 9 a.

a 3215 3216 3218 3231 3235 3244 3249 3250 3251 3.253 3254 3259 3260 3261 15 3262 3284 3285 3290 3292 20 3293 3306 3307 3310 3333 3334 3336 3337 3338 3339 3341 3363 3364 3370

CCULJGUAG

UCCUUGUA

GCUCCUUG

UCCAUAGU

AUCUUCCA

AGAAAUCA

CUGUAAGA

ACUGUAAG

AACUGUAA

AAAACUGU

GAAAACUG

CACUUGAA

CCACUUGA

GCCACUTUG

GGCCACUU

AAGACAGG

GAAGACAG

UUCUGGAA

CUUUCUGG

ACUIJUCUG

UCCCGAUG

GUCCCGAU

CAGGUCCC

GAUAAAAG

AGAUAAAA

UCAGAUAA

CUCAGAUA

UCUCAGAU

UUCUCAGA

UGUUCUCA

AAAUCACA

AAAAUCAC

AAGGCCAA

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 AACCGUCA GAA AAACCGUC GAA AG.AAACCG 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 AUG CACUU GAA AAUGCACU GAA AUGAAUGC GAA AUGUUIJCU GAA AAUGUUUC GAA AGAAUGUIJ GAA AAGAAUGU GAA AAAGAAUG GAA AAAAGAAU GAA AUAAAAGA GAA AUCUUCAC GAA AAUCUUC~rA GAA AUCACAAA

UGACGGUUU

GACGGUUUC

CGGIJUUCUA

GAG CCCAUC

CCAUCACUA

UGGAAGAUC

GAUCUGAUU

AUCUGAUUU

UCUGALTUUC

UGAUUUCUU

GAUUTUCUUA

CUUACAGUU

UTUACAGLUU

UACAGLTUU

ACAGUUUTUC

CAUGGAGUU

AUGGAGUUC

GUUCCUGUC

UCCUGUCUU

CCUGUCUUC

AAGUGCAUU

AGUGCAUUC

GCALIJCAUC

AGAAACALU

GAAACAUTUC

AACAUUCUU

ACAUTUCUUU

CAUTUCUUUUT

AUTUCUEJUA

UCUUUTJAUC

GUGAAGAUU

UGAAGALUU

LTUUGUGALU

CUACAAGG

UACAAGGA

CAAGGAGC

ACUAUGGA

UGGAAGAU

UGAUUUCU

UCUUACAG

CL7UACAGU

UUACAGUU

ACAGUUUU

CAGUtUUC

UUCAAGUG

UCAAGUGG

CAAGUGGC

AAGUGGCC

CCUGUCUU

CUGUCUUC

UUCCAGAA

CCAGAAAG

CAGAAAGU

CAUCGGGA

AUCGGGAC

GGGACCUG

CUUUUAUC

UUtJUAUCU

LUAUCUGA

UAUCUGAG

AUCUGAGA

UCUGAGAA

UGAGAACA

UGUGAUUUL

GUGALUTU

UUTGGCCLU

4 6 3371 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 3533

CAAGGCCA

GCAAGGCC

UCCCGGGC

CUUAUAAA

UtJCUUAUA

GILTCUUAU

GGLUCUUA

GGGGUUCU

UCUCACAU

UIJCUCACA

AAGtJCGAG

AGGAAGUC

UUCAGAGG

UUUJCAGAG

CCAUUUCA

AGAUUCGG

CAAAGAUA

GUCAAAGA

LTUGUCAAA

UUUILJGUCA

AUUUUGUC

GUGCUGUA

UGGUGCUG

CUCCGUAA

UACUCCGU

AUACUCCG

CACAGCAA

CCCACAGC

AAGGAGAA

CUAAGGAG

CCUAAGGA

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 GAA AAGUCGAG GAA AGGAAGUC GAA AGCCAUCC GAA AUUCGGGA GAA AGAUUCGG GAA AUAGAUUC GAA AGAUAGAU GAA AAGAUAGA GAA AUUIJUGUC GAA AGAUUJUUG GAA ACCACACG GAA AGACCACA GAA AAGACCAC GAA ACUCCGUA GAA AUACUCCG GAA AUUUCCCA GAA AGAUUUCC GAA AAGAUUTUC GAA AGAAGAUU GAA AGGAGAAG CUGAUGA X GAA AAUCACAA CUGAUGA X GAA AAAUCACA CUGAUGA X GAA AGGCCAAA CUGAUGA X GAA AUCCCGGG CUGAUGA X GAA AUAUCCCG CUGAUGA X GAA AAUAUCCC CUGAUGA X GAA AAATJAUCC CUGAUGA X GAA AUAAAUAU CUGAUGA X GAA AUCGGGGU CUGAUGA X GAA AAUCGGGG CUGAUGA X GAA AUCUCCUU CUGAUGA X GAA AGUAUCUC CUGAUGA X GAA AGUCGAGU UUGUGAUUU

UGGCCUTUG

UGUGAUUUU

GGCCUUGC

UUUGGCCUU

GCCCGGGA

CCCGGGAUA UUUEAUAAG CGGGAUAUU UAUAAGAA GGGAUAUUU AUAAGAAC GGAUAUUUA

UAAGAACC

AUAUUUAUA AGAACCCC ACCCCGAUU AUGUGAGA CCCCGAUUA UGUGAGAA AAGGAGAUA CUCGACU GAGAUACUC GACUTUCCU ACUCGACUU CCUCUGAA CUCGACUUC CUCUGAAA GACUUCCUC UGAAAUGG GGAUGGCUC CCGAAUCU UCCCGAAUC UAUCUUUG CCGAAUCUA

UCUUUGAC

GAAUCUAUC UUUGACAA AUCUAUCUU UGACAAAA UCUAUCUUU GACAAAAU GACAAAAUC UACAGCAC CAAAAUCUA CAGCACCA CGUGUGGUC UUACGGAG UGUGGUCUU

ACGGAGUA

GUGGUCUUA CGGAGUAU UACGGAGUA UUGCUGUG CGGAGUAUU GCUGUGGG UGGGAAAUC

UUCUCCUU

GGAAAUCUTU CUCCUUAG GAAAUCUUC UCCUTUAGG AAUCUUCUC CUTUAGGUG CUUCUCCUU AGGUGGGU CACCUAAG CUGAUGA X ACCCACCU CUGAUGA X *4 f3 4444Sf 3534 3542 3544 3548 3558 357S 3576 3577 3583 3613 3620 3623 3625 3628 3636 3638 3640 3645 3689 3690.

3699 3711 3718 3719 3723 3724 3735 3748 3755 3759 3765 3774 3787

GACCCACC

GGIJAUGG.A

UGGGUAUG

CUCCUGGG

UCCAUUTUG

GACUGCAA

CGACUGCA

GCGACUGC

CCUCAGGC

GUACUCAG

GAGUAGAG

CAGGAGUA

UJUCAGGAG

GAUUUCAG

AUCUGAUA

UGAUCUGA

CAUGAUCU

UCCAGCAU

GTJUCUGCA

AGUUCUGC

UtJUUCCAC

AAAUCACC

LTUGAAGCA

CUUGAAGC

UTUUGCUUG

AUILJUGCU

UCCUGUUG

GUAGUCUUT

UUGGGAUG

UUGAUUGG

AUGGCAUU

CCUGUCAG

AAACCCAC

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

CGAA AAGGAGAA C GAA ACCCACCU [GAA AGACCCAC GAA AUGGAGAC GAA ACUCCUGG GAA AGUCCUCA GAA AAGUCCUC GAA AAAGUCCU *GAA ACUGCAAA *GAA AGCUCUCA GAA ACUCAGGA GAA AGUACUCA GAA AGAGUACU GAA AGUAGAGU GAA AUUUCAGG GAA AGAUUCA GAA AUAGAUU GAA AUCUGAUA GAA AUCUUGGC GAA AAUCUTUGG GAA AGUUCUGC GAA AGUUUTUUC GAA AUCACCUA GAA AAUCACCU GAA AGCAAAUC GAA AAGCAAAU GAA ACAUTUUGC GAA ACCAUCCU GAA AGUCUUUA GAA AUGUAGUC GAA AUUGGGAU GAA AUGGCAUU GAA AUUUCCUG UUCUCCUIJ7

AGGUGGGUC

GUGGGUCUC

GUCUCCAUP

CCAGGAGUP

UGAGGACUCL

GAGGACULU

AGGACUUUU

UUUGCAGJC

UGAGAGCUC

UCCUGAGUA

UGAGUACUC

AGUACUCUA

ACUCUACUC

CCUGAAAUC

UGAAAUCUA

AAAUCUAUC

UAUCAGAUC

GCCAAGAUU

CCAAGAULU

GCAGAACUU

GAAAAACUA

UAGGUGAUU

AGGtJGAUUU

GAUUUGCUU

AUUUGCUUC

GCAAAUGUA

AGGAUGGUA

UAAAGACUA

GACUACAUC

AUCCCAAUC

AAUGCCAUA

CAGGAAAUA

GGUGGGUC

UCCAUACC

CAUACCCA

CCCAGGAG

LCAAAUGGA

FUUGCAGUC

rUGCAGUCG

GCAGUCGC

GCCUGAGG

CUGAGUAC

CUCUACUC

UACUCCUG

CUCCUGAA

CUGAAAJC

UAUCAGAU

UCAGAUCA

AGAUCAUG

AUG CUGGA

UGCAGAAC

GCAGAACU

GUGGAAAA

GGUGAUUJ

UGCLTLJCAA

GCUUCAAG

CAAGCAAA

AAGCAAAU

CAACAGGA

AAGACUAC

CAUCCCAA

CCAAUCAA

AAUGCCAU

CUGACAGG

GUGGGULU

3794 AGUAUGUA CUGAUGA X GAA ACCCACUA

S

S. 5

C

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

GAGUAUGU

UGAGUAUG

GAGUUGAG

CAGGAGLU

GAAGGCAG

CCUCAGAG

UCCUCAGA

AGUCCUCA

CCtJUGAAG

UCCUTUGAA

UJUUCCUUG

Cu.UUCCuTU

AGCUGAAA

GGAGCUGA

CGGAGCUG

UCGGAGCU

AAACUTUCG

CUGAAUTUA

CCUGAAUU

UCCUGAAU

GCUUCCUG

AGCULJCCU

CAUCAUCA

ACAUAUCU

CAUUUACAC

AAAGCALUU 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 'UGAUGA X "UGAUGA X 'TJGAUGA X -7JGAUGA X 'UGAUGA X .TGAUGA XC ~UGAUYGA XC GAA AACCCACU GAA AAACCCAC GAA AUGUAAAC GAA AGUAUGUA GAA AGUUGAGU GAA AGGCAGGA GAA AAGGCAGG GAA AGAAGGCA GAA AGUCCUCA GAA AAGUCCUC GAA AGAAGUCC GAA AAGAAGUC GAA ACUUUCCU GAA AUACUUUC GAA AAUACUUU GAA AAAUACUU GAA AGCUGAAA GAA ACUUCGGA GAA AACUIJCGG GAA AAACUUCG 3AA AUUAAACU 3AA AAUTUAAAC 3AA AGCUUCCU MAA ACAUCAUC ,AA AUCUGACA ;AA ACAUAUCJ UAGUGGGUU UACAUACU AGUGGGUUU ACAUACUC GUGGGUUUA CAUACUCA GUUUJACAUA CUCAACUC UACAUACUC AACUCCUG ACUCAACUC CUGCCUUC UCCUGCCUU CUCUGAGG CCUGCCUUC UCUGAGGA UGCCUUCUC UGAGGACU UGAGGACUU CtTUCAAGG GAGGACUUC tJUCAAGGA GGACUUCtJU CAAGGAAA GACUUCUTUC AAGGAAAG AGGAAAGUA UUUCAGCU GAA.AGUAkUE UCAGCUCC AAAGUAUUU CAGCUCCG AAGUAUUUC AGCUCCGA UEJUCAGCUC CGAAGUUU UCCGAAGUIJ UAAUTUCAG CCGAAGUUTU AAUtJCAGG CGAAGIJUUA AUUCAGGA AGUUUAAUU

CAGGAAGC

GLUEJAAUTUC AGGAAGCU AGGAAGCUC UGAUGAUG GAUGAUGUC

AGAUAUGU

UGUCAGAUA UGUAAAUG AGAUAUGUA

AAUGCUUU

UAAAUGCUTU UCAAGUUTC AAAUGCUU CAAGUUCA AAUGCUUUC AAGUUCAU UUTUCAAGUTU

CAUGAGCC

UUCAAGUUC AUGAGCCU GAAAGAAUC AAAACCUU GAACUUGA CUGAUGA X GAA AGCAUUtUA UGAACUUG CUGAUGA X GAA AAGCAUUU AUGAACUU CUGAUGA X GAA AAAGCAUU GGCUCAUG CUGAUGA X GAA ACUUGAAA AGGCUCAU CUGAUGA X GAA AACUUGAA AAGGU=J CUGAUGA X GAA AULJCUUUC 3932 3933 3942 3943 S 3944 3945 3959 3965 3966 10 3974 3994 3998 4004 4006 4022 4023 4052 4056 4062 4067 4074 4081 4087 4094 4103 4110 4123 4124 4125 4132 4133 4149

GUUCUUCA

AGLUtCUUC

UUCGGUAA

AUUCGGUA

CAUTJCGGU

GCAUUCGG

CAAACAUG

AGUCAUCA

UAGUCAUC

CGCCCUGG

GGCCAACA

GAGAGGC C

GCAUGGGA

CAGCAUGG

UCCAGGUG

GUCCAGGU

UCUUGAGC

UCAAUCUU

CUCAAGUC

UUACUCUC

UIJACUGGU

CUUACUUU

CGACUCCU

ACAGCCCC

UGACAUCA

GGCCUGCU

AUGGCAGA

AAUGGCAG

GAAUGGCA

ACAGCUGG

CACAGCUG

CCLUTCGCU

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 AGGUUUUG GAA AAGGULUU 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 AGCGCUUC 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 GAA ACCUGCGC CAAAAC CU)

AAAACCUU

GAAGAACIJ

AAGAACUU

AGAACUTUUU

GAACUUUTUA

UGCCACCUC

CUCCAJGLU

UCCAUGUUU

UGAUGACUA

GCAGCACUC

CACUCUGU

GUUGGCCUC

UGGCCUCUC

GAAGCGCUU

AAGCGCUUIC

CAAGGCCUC

GCCUCGCUC

CUCAAGAUU

GAUUGACUU

UUGAGAGUA

UAACCAGUA

GUAAAAGUA

UAAGGAGUC

GGGGCUGUC

UCUGAUGUC

GGCCCAGUU

GCCCAGUU

CCCAGUUUC

UCUGCCAUU

CUGCCAtJUC

GGGCACGUC

GCGCAGGUU

UGAAGAAC

GAAGAACU

UUTACCGAA

UACCGAAU

ACCGAAUG

CCGAAUGC

CAUGLTUUG

UGAUGACU

GAUGACtJA

CCAGGGCG

UGUUGGCC

GGCCUCUC

UCCCAUGC

CCAUGCUG

CACCUGGA

ACCUGGAC

GCUCAAGA

AAGAUTUGA

GACUEJGAG

GAGAGUAA

ACCAGUAA

AAAGUAAG

AGGAGUCG

GGGGCUGU

UGAUGUCA

AGCAGGCC

UCUGCCAU

CUGCCAUJ

UGCCAUTUC

CCAGCUGU

CAGCUGUG

AGCGAAGG

CACCUACG

4169 CGUAGGUG CUGAUGA X 4170 4175 4203 4214 4229 4235 4242 4247 4250 10 4263 4265 4270 4271 4284 4285 4287 4288 4289 4291 4305 4307 4308 4309 4311 4325 4329 4330 4331 4338 4340 4341 4347

UCGUAGGL

CGUGGUCG

CAGCACGC

GGGGCGGG

CCGAGUUG

GGACCACC

GAGUACAG

GGGUGGAG

GUGGGGUG

AAACUCUA

UCAAACUC

UCGUGUCA

UUCGUGUC

CUAGAAAU

UCUAGAAA

CUUCUAGA

GCUUCUAG

UGCUUCUA

UGUGCUUC

GGUAUAAA

GGGGUAUA

GGGGGUAU

UGGGGGUA

CCUGGGGG

GCAAAAGC

ACUGGCAA

UACUGGCA

AUACUGGC

AUGCAUAA

AUAUGCAU

UAUAUGCA

AACUUAUA

rCUGAUGA

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

X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA

AACCUGCG

AGGUGAAC

AUUTJLTCCU

AGCAGCAC

AGUCUGGG

AGUTUGUAG

ACCACCGA

ACAGGACC

AGUACAGG

AUGGGUGG

AGAUGGGU

ACUCUAGA

AACUCUAG

AGGCUUCG

AAGGCUUC

AUAAGGCU

AAUAAGG C

AAAUAAGG

AGAAAUAA

ACACAUGU

AUACACAU

AAUACACA

AAAUACAC

AUAAAUAC

AGUUUCCU

AGCUAGLJU

AAGCUAGU

AAAGCUAG

ACUGGCAA

AUACUGGC

AAUACUGG

AUGCAUAA

CGCAGGUULC

GUUCACCUP

AGGAAAAUC

GUGCUGCUC

CCCAGACUA

CUACAACUC

UCGGUGGUC

GGUCCUGUA

CCUGUACUC

CCACCCAUC

ACCCAUCUA

UCUAGAGUU

CUAGAGUUU

CGAAGCCUU

GAAGCCUTUA

AGCCUTJAUU

GCCUUAUUU

CCUTUAUUTUC

UUAUUUCUA

ACAUGUGUA

AUGUGUAUU

UGUGUAUUUI

GUGUAUUTUA

GUAUUUAUA

AGGAAACUA

AAICUAGCUU

ACUAGCUUEJU

CUAGCUUUJ

UUIGCCAGUA

GCCAGUALU

CCAGUAUTUA

UtJAUGCAUA

ACCUACGA

CGACCACG

GCGUGCUG

CCCGCCCC

CAACUCGG

GGUGGUCC

CUGUACUC

CUCCACCC

CACCCCAC

UAGAGLIJU

GAGUUUGA

UGACACGA

GACACGAA

AUUUCUAG

UUUCUAGA

UCUAGAAG

CUAGAAGC

UAGAAGCA

GAAGCACA

UUUAUACC

UAUACCCC

AUACCCCC

UACCCCCA

CCCCCAGG

GCUUUUJTGC

UUGCCAGU

UGCCAGUA

GCCAGUAU

UUAUGCAU

AUGCAUAU

UGCAUAUA

UAUAAGTU

4349 UAAACUUA CUGAUGA X GAA AUAUGCAU AUCUUAAGUA AUGCAUAUA UAAGUUUA

S

S.

*S.S

S

S.

4351 4355 4356 4357 4363 4364 4365 4367 4369 10 4370 4371 4389 4390 4391 4392 4398 4399 4400 4401 20 4402 4403 4404 4407 4413 4414 4415 4416 4417 4418 4419 4420 4421

UGUAAACI

AAGGUGUI

AAAGGUGI.

TJAAAGGUC

GAAAGAUI

GGAAAGAt.

UGGAAAG~z

CAUGGAAP

CCCAUGGP

UCCCAUGG

CUCCCAUG

AUCACAAA

AAUCACAA

AAAUCACA

AAAAUCAC

AUUAAAAA

UAUUtAAAA

CUAUUAAA

ACUAUUAA

CACUAUUA

GCACUATU

AGCACUAU

AAAAGCAC

AAAAAAAA

AAAAAAAA

CAAAAAAA

UCAAAAAA

GUCAAAAA

AGIJCAAAA

UAGUCAAA

UUAGUCAA

GUTJAGUCA

J CUGAUGA

SCUGAUGA

J CUGAUGA

;CUGAUGA

CUGAUGA

I CUGAUGA

LCUGAUGA

LCUGAUGA

CUGAUGA

CUGAtJGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGALYGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA I GAA AUAUAUGC CGAA 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 AUUJAAAAA GAA AGCACUAU GAA AAGCACUA GAA AAAGCACU GAA AAAAGCAC GAA AAAAAGCA GAA AAAAAAGC GAA AAAAAAAG GAA AAAAAAAA GAA AAAAAAAA

GCAUAUAUI

AUAUAAGL

UAUAAGUUL

AUAAGUUU7

UUACACCUC

UACACCUUL-

ACACCUUUP

ACCUUUAUC

CUUUAUCULJ

UUUAUCUJU

UUAUCUUUC

CAGCUGCUU

AGCUGCUUEJ

GCUGCUULU

CUGCUUUUU

UUJUGUGALTJ

UTUGUGAUUU

UGUGAUUUU

GUGAUTUUUU

UGAUUUUUUJ

GAUUUUUU

AUULUUUUA

UUTUUUAAUA

AUAGUGCUU

UAGUGCUU

AGtJGCUUUU

GUGCUUJUU

UGCUUTUUUU

GCJUUUULU

CTUUUUUU

UUUU-UUUUu

UUUUUUUUU

k. AGUUIJACA

JUACACCUU

J ACACCUU

CACCUUUA

YUAUCULUC

IAUCUUUCC

UCUUUJCCA

LTUUCCAUG

UCCAUGGG

CCAUGGGA

CAUGGGAG

UJUGUGAU

UUTGUGAUU

UGUGAULU

GUGAUUUUT

UIUUUAAU

UUUTUAAUA

tJUUAAUAG

UUAAUAGU

UAAUAGUG

AAUAGUGC

AUAGUGCU

GUGCUULJ

UULTtUUU

LUUUUUU

JTUUUUG

UUUUUtJGA

UUUUTUGAC

UUUUGACU

UUUGACUA

UTUGACUAA

UGACUAAC

S

S

S

4422 UGUUAGUC CUGAUGA X GAA AAAAAAAA

UUUUUGCAC

UUUUUUUUU GACUAACA 4427 AUUCUtJGU CUGAUGA X GAA AGUCAAAA Ut.JGCAAAGU UUUUGACUA

ACAAGAAU

4438 4442 4448 4456 4476 4482 4486 4489 10 4494 4495 4498 4504 4505 4513 4516 4517 4520 4533 4534 4541 4557 4576 4577 4581 4598 4610 4615 4664 4665 4678 4700 4702

UCUGGAGI

UCUAUCUC

UAUIJUCUC

CUUGUCAC

UUUAGCAC

UGAGGAUL

AACAUGAC

AGUAACAL

CACUGAGIU

ACACUGAG

CUAACACU

AUUIJCUCU

GAUUUCUC

UIJAGGAAG

GGUUUAGG

GGGUUUAG

AUUGGGUU

GAGCAGGG

GGAGCAGG

GGGGGUUG

CGUGCCCU

CUCAAUCA

CCUCAAUC

AGCUCCUC

CAUUGGGU

GGGUACGU

CAGUGGGG

CUGGGGCU

CCUGGGGC

CAGCCAGU

ACUCCCGA

GGACUCCC

J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

J CUGAUGA

;CUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA,

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA I CUGAUGA CUGAUGA CUGAUGA CUGAUGA CUGAUGA Y C GAA ACAUTUCU IGAA AGUUACAU GAA AUCUGGAG GAA AUUUCUCU GAA AGUGUUCU GAA AGCAGUAG GAA AIJUUAGCA GAA AGGAUUUA GAA ACAUGAGG GAA AACAUGAG GAA AGUAACAU GAA ACACUGAG GAA AACACUGA GAA AUUUCUCU GAA AGGAUUTUC GAA AAGGAULU GAA AGGAAGGA GAA AGUCAUtJG GAA AAGUCALJU GAA AGCAGGGA GAA AGGUGGCG GAA ACUGGUCC GAA AACUGGUC GAA AUCAAACU GAA AUCAGUGC GAA AUG CAUUIG GAA ACGUGAUG GAA ACGGGCUU GAA AACGGGCU GAA AUCCCCUG GAA AUGUUGCU GAA AGAUGUUG

AAGAAUGU

AUGUAACU

CUCCAGAUM

AGAGAAAU2

AGAACACU)

CUACUGCU)

UGCUAAAUC

UAAAUCCUC

CCUCAUGUL

CUCAUGUU;

AUGUUACUC

CUCAGUGUL

UCAGUGUUA

AGAGAAAUC

GAAAUCCUJ

AAAUCCUUC

UCCUUCCUA

CAAUGACUU

AAUGACUUC

UCCCUGCUC

CGCCACCUC

GGACCAGUU

GACCAGUUU

AGUUUGAUU

GCACUGAUC

CAAUGCAUC

CAUCACGUA

AAGCCCGUU

AGCCCGUUA

CAGGGGAUC

AGCAACAUC

CAACAUCUC

Pi ACUCCAGA

CAGAUAGA

~GAGAAAUA

~GUGACAAG

'CUGCUAAA

k. AAUCCUCA

CUCAUGUU

AUGUUACU

JACUCAGUG

CUCAGUGU

AGUGUTUAG

AGAGAAAU

GAGAAAUC

CUUCCUAA

CCUAAACC

CUAAACCC

AACCCAAU

CCCUGCUC

CCUGCUCC

CAACCCCC

AGGGCACG

UGAUUGAG

GAUTUGAGG

GAGGAGCU

ACCCAAUG

ACGUACCC

CCCCACUG

AGCCCCAG

GCCCCAGG

ACUGGCUG

UCGGGAGU

GGGAGUCC

4709 UGCUAGAG CUGAUGA X GAA ACUCCCGA UGGGCCCAC UCGGGAGUC CUCUAGCA 4712 4714 4 723 4802 4803 4840 4852 4853 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

GCCUGCUI

AGGCCUGC

ACAUGUC.

GCGUCUCI

UGCGUCUC

GCAUTUGCL

GCCACUGP

AGCCACUG

AAGCCACU

GAGCUGGG

AGAGCUGG

AAGGGUCA

AAAUGUAG

CAAAUGUA

CUCAAAUG

GGCCCUCA

GGGCCCUC

AUCCAGAA

AAUCCAGA

GAAUCCAG

AGAAUCCA

CCUCCCAG

GCCUCCCA

AAAAAAGA

CCAAAAAA

UJUCCAAAA

GUUCCAAA

AGUUCCAA

UAGUUCCA

UUAGUUICC

AUUUGCUUI

AGGUCUAA

k. CUGAUGA

_CUGAUGA

J CUGAUGA L 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 I CUGAUGA2

CUGAUGA)

CUGAUGA

GAA AGGACUCC GAA AGAGGACU GAA AGGCCUGC GAA AUUCUUUC GAA AAUUCUUJ GAA AGCCCCGU GAA AUGGCALU GAA AAUGGCAU GAA AAAUGGCA GAA AGCCACUG GAA AAGCCACU X GAA AGCUGGGA GAA AGGGUCAG GAA AAGGGUCA X GAA AGAAGGGU X GAA AUGtJAGAA X GAA AAUGUAGA X GAA AUGUCCCC X GAA AAUGUCCC X GAA AAAUGUCC K GAA AAAAUGUC K GAA AUCCAGAA K GAA AAUCCAGA K GAA AUUUGUCC CK GAA AUAUUUGU K GAA AGAUAUUU GAA AAGAUAUU C GAA AAAGAUAU C GAA AAAAGAUA C GAA AAAAAGAU r GAA

AGUUCCAA

CGAA AUUUGCUU

GGAGUCCU(

AGUCCUCUZ

GCAGGCCUI

GAAAGAAU.

AAAGAAUUT.

ACGGGGCUC

AAUGCCAUL

AUGCCAUUL

UGCCAUUUC

CAGUGGCUU

AGUGGCUUC

UCCCAGCUC

CUGACCCIU

UGACCCUUC

ACCCUUCUA

UUCUACAUU

UCUACAUUU

GGGGACAUU

GGGACAUUU

GGACAUUUU

GACAUTJUUC

UIJCUGGALU

UCUGGAUtJC

GGACAAAUA

ACAAAUAUC

AAAUAUCLU

AAUAUCUUU

AUAUCUUUU

UAUCUUtUU

AUCUUUUIIU

UUJGGAACUA

AAGCAAALTLU

_UAGCAGGC

k. GCAGGCCU kAGACAUGU

JUGAGACGC

JGAGACGCA

AGCAAUGC

TUCAGUGGC

CAGUGGCU

.AGUGGCUU

CCCAGCUC

CCAGCUCU

UGACCCUU

CUACAUUUJI

UACAUULUG

CAUJUUGAG

UGAGGGCC

GAGGGCCC

UUCUGGAU

UCUGGAUU

CUGGAUUC

UGGAUTUCU

CUGGGAGG

UGGGAGGC

UCUUUTU

ULUULTUGG

UUUtJGGAA

UUUGGAAC

UUGGAACU

UGGAACUA

GGAACUAA

AAGCAAAU

UUAGACCU

S 5 4988 AAGGUCUA CUGAUGA X GAA AAUUUGCU a a a a 4989 4990 4996 4997 4998 5002 5013 5014 5016 5020 5024 5025 5027 5030 5031 5041 5042 5043 20 5047 5048 5051 5069 5074 5084 5087 5088 5089 5094 5097 5099 5102

AAAGGUCU

UAAAGGUC

CAUAGGUA

CCAUAGGU

UCCAUAGG

CACUUCCA

GGACAUAG

UGGACAUA

AAUGGACA

UGAGAAUG

CGAAUGAG

ACGAAUGA

CCACGAAU

AUGCCACG

CAUGCCAC

CAAAUCAA

ACAAAUCA

UACAAAUC

GUGCUACA

AGUGCUAC

CUCAGUGC

UCAGAGITJ

UGGGCUCA C

GCCAAAAGC

GGAGCCAAC

AGGAGCCA C

GAGGAGCCC

UACUAGAGC

UCUUACUA C

CAUCUACC

GUGCAUCU 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 CJGAUGA X CUGAUGA X :UGAUGA X 'UGAUGA X UTGAUGA X ~UGAUGA X .TGAUGA XC .TUGAUGA X UGAUGA XC .UGAUGA XC 'UGAUGA XC 'UGAUGA X UJGAUGA X UGAUGA X GAA AAAUTUUGC GAA AAAAUJUG GAA AGGUCUAA GAA AAGGUCUA GAA AAAGGUCU GAA AGGUAAAG GAA ACCACUJC GAA AACCACUU GAA AGAACCAC GAA ACAUAGAA GAA AUGGACAU GAA AAUGGACA GAA AGAAUGGA GAA AUGAGAAU GAA AAUGAGAA GAA ACAUGCCA GAA AACAtJGCC GAA AAACAUGC 3AA AUCAAAAC .AA AAUCAAAA 3AA ACAAAUCA 3AA AGUGCCAC 3AA AGUtJGAGU ;AA AUGGGCUC 'AA AGUAUGGG 'AA AAGUAUGG 'AA AAAGUAUG A AGCC.AAAA 'AA AGGAGCCA 'AA AGAGGAGC 'AA ACUAGAGG AGCAAAUUU

UAGACCUU

GCAAAUUUU

AGACCUUU

CAAAUUIJUA

GACCUUUA

UUAGACCUTU

UACCUAUG

UAGACCUJU

ACCUAUGG

AGACCUUUA

CCUAUGGA

CUUUACCUA

UGGAAGUG

GAAGUGGUU

CUAUGUCC

AAGUGGUUC

UAUGUCCA

GUGGUEJCUA

UGUCCAUU

UTUCUAUGUC CAUtJCUCA AUGUCCATJU

CUCAUUCG

UGUCCAUUC UCAtJUCGU UCCAUUCUC

AUUCGUGG

AUUCUCAUU

CGUGGCAU

UUCUCAUUC

GUGGCAUG

UGGCAUGUU

UUGAIUUG

GGCAUGUUU

UGALUJUGU

GCAUGUUUU GAUUtJGUA G~tLTUMGAUU

UGUAGCAC

UUUtJGAUUU

GUAGCACU

UGAUUtJGUA

GCACUGAG

GUGGCACUC

AACUCUGA

ACUCAACUC

UGAGCCCA

GAGCCCAUA

CUUUUGGC

CCCAUACJU

UIJGGCUCC

CCAUACUUJ

UGGCUCCU

CAUACUJUU

GGCUCCUC

UUUUGGCUC

CUCUAGUA

UGGCUCCUC

UAGUAAGA

GCUCCUCUA

GUAAGAUG

CCUCUAGUA

AGAUGCAC

UGAAAACUrJ AGCCAGAG 5119 CUCUGGCU CUGAUGA X GAA AGUUUUCA

S

S

5120 5129 5130 5134 5137 5139 5156 5157 5170 5175 5176 5178 5180 5181 5182 5187 5189 5190 5193 20 5195 5197 5200 5209 5210 5214 5218 5219 5220 5222 5226 5228 5229 5231

ACUCUGGC

GACAACCU

AGACAACC

CUGGAGAC

GGCCUGGA

AUGGCCUG

UUCAGUGU

UUTUCAGUG

UAGAAUGU

CAAAAUAG

CCAAAAUA

ACCCAAAA

AUACCCAA

AAUAC CCA

UAAUACCC

UAUALTUAA

UAUAUALU

CUAUAUAU

GGACUAUA

CUGGACUA

GUCUGGAC

AGUGUCUG

AUUtGAGUU

AAILTJGAGU

AAGAAAUUT

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 AAGUUJUUC GAA ACUCUGGC GAA AACUCUGG GAA ACCUAACU GAA ACAACCUA GAA AGACAACC GAA AGGCCAUC GAA AAGGCCAU GAA ACAUUUUC GAA AUGUGACA GAA AAUGUGAC GAA AGAAUGUG GAA AUAGAAUG GAA AAUAGAAU GAA AAAUAGAA GAA ACCCAAAA GAA AUACCCAA GAA AAUACCCA GAA AUUAAUAC GAA AUAtJUAAU GAA AUAUAUUA GAA ACUAUAUA GAA AGUGUCUG GAA AAGUGUCU GAA AGUUAAGU GAA AtJUGAGUU GAA AAUUGAGU GAA AAALJUGAG GAA AGAAAUUG GAA ACCAAGAA GAA AUACCAAG GAA AAUACCAA GAA AUAAUACC

GAAAACUTUA

GCCAGAGLU

CCAGAGUJIA

AGUITJAGGUU

UAGGUUGUC

GGUUGUCUC

GAUGGCCUU ACACUGAA AUGGCCUUA CACUGAAA GAAAAUGUC ACAUUCUA UGUCACAUUI CUAUUUUG GUCACAUUC UALTUUUGG CACAUUCUA UUUUGGGU CAUUCUAUTU UUGGGUAU AUUCUAUUU UGGGUAUU UUCUAUUUU GGGUALTIJA UUUUGGGUA UUAAUAUA UTUGGGUAUTU AAUAUAUA UGGGUAUUA AUAUAUAG GUAUUAAUA UAUAGUCC AUTUAAUAUA UAGUCCAG UAAUAUAUA GUCCAGAC UAUAUAGUC CAGACACU CAGACACUU AACUCAAU AGACACtJUA ACUCAAUU ACUUAACUC AAUUUCLU AACUCAAUUt UCUUGGUA ACUCAAUUIJ CUUGGUAU CUCAAUUUTC UUGGUAUU CAAUTUUCUU GGUAUUAU UUCUUGGUA UUAUUCUG CUTUGGUAUTU ALUUGUU UTUGGUAUUJA UTUCUGULU GGUAUUAUU CUGUUUUG

GCCAGAGU

AGGUUGUC

GGUUGUCU

GUCUCCAG

UCCAGGCC

CAGGCC!AU

5232 GCAAAACA CUGAUGA X GAA AAUAAUAC GAUUCUttUG GUAUUAUUC

UGUUUUGC

a 5236 5237 5238 5246 5247 5250 5284 5296 5297 5298 5299 5301 5305 15 5307 5336 5340 5345 5361 5363 5365 5367 5382 5383 5395 5417 5421 5426 5427 5428 5431 5432

*CUGUGCA

ACUGUGC

AACUGUG

UCACAAC'

UUCACAAi

UCUJUUCA

CUCCUCA(

AUGGAGA.

UAUGGAGJ

AUAUGGAC

GAUAUGGI

UUGAUAUC

CGUUUUG~z

CUCGUIJUL

ACCUUAUU

CUITJGACCU)

CuTUCCCUu

GGUAUAGA

UUGGUAUA

GGUUGGUA

UUGGUUGG

UGUUGGUG

GUGUIJGGU

UGGGUCCC

ACGUGACU

GGAAACGU

GAAAAGGA

UGAAAAGG

AUGAAAAG

UAAAUGAA

UtJAAAtJGA A CUGAUGA A CUGAUGA C CUGAUGA UI CUGAUGA 2CUGAUGA 7CUGAUGA 3 CUGAUGA

CUGAUGA

k. CUGAUGA 3CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA2 CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA X~ CUGAUGA X~ CUGAUGA X CUGAUGA X 2 2 x x x x x x x x X GA X GA X GA K GA K GA K G,.

'C GA.

'GAI

GAZ

GA;

GA.

GA.P

GAZ

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

AACAGAAUA

AAACAGAAU

~AAACAGAA

~ACUGUGCA

~AACUGUGC

~ACUAACUG

~ACUGCAUU

'ACUCUCCU

~AACUCUCC

SAAACUCUC

AAAACUCU

AGAAAACU

AUGGAGAA

AUAUGGAG

ACCULTLJJU

AUUGACCU

ACCUUAUU

ACGGGGUC

AGACGGGG

AGAGACGG

AUAGAGAC

AUUGGUUU

AAUUGGUU[

ACUGUGUU

ACTJUCCUG

ACUGACUU

ACGUGACU

AACGUGAC

AAACGUGA

AGGAAACG

AAGGAAAC

UAUUCUGU

AIJUCUGUU

LJUCUGUUU

UGCACAGU

GCACAGUU.

CAGUUAGU

AAUGCAGU

AGGAGAG~L7

GGAGAGUM~

GAGAGUULt

AGAGUUUU(

AGUUUUCJC

IJTJCUCCAUI

CUCCAUAUC

AAAAAGGUC

AGGUCAAUA

AAUAAGGUC

GACCCCGUC

CCCCGUCUC

CCGUCUCUA

GUCUCUAUA

AAACCAAUU

AACCAAUUjC

AACACAGUU

CAGGAAGUC

AAGUCAGUC

AGUCACGUU

GUCACGUEJU

UCACGUTUUC

CGUUTUCCUU

GUUUCCUUU

U UUGCACAG U UGCAcAGU U GCACAGUU U AGUUGUGA A~ GUUGUGAA LI GUGAAAGA

:CUGAGGAG

J UUCUCCAU J UCUCCAUA J CUCCAUAU

UCCAUAUC

CAUAUCAA

UCAAAACG

AAAACGAG

*AAUAAGGU

AGGUCAAG

*AAGGGAAG

UCUAUACC

UAUACCAA

UACCAACC

CCAACCAA

CACCAACA

ACCAACAC

GGGACCCA

AGUCACGU

ACGUUICC

UCCLUUUC

CCUUUUCA

CUUUUCAU

LTUCAUUTUA

UCAUUTUAA

5433 AUUAAAUG CUGAUGA X GAA AAAGGAAA UUUCCUUUU CAUUIJAAU 5434 5437 5438 5439 5448 5449 5454 5456 5458 10 '5464 5467 5489 5490 5501 5503 5504 5511 5512 55.13 20 5518 5521 5526 5537 5541 5544 5545 5546 5555 5557 5558 5559 5561 5566

CAUTUAAAU

CCC CAUTUA

UCCCCAUU

AUCCCCAU

GAUAGUGG

AGAUAGUG

GUGUGAGA

UAGUGUGA

AUTUAGUGU

UULUCAGAU

UCCUUUCA

CGCCAGCU

GCGCCAGC

GUGCUUAA

AAGUGCUU

AAAGUGCU

GGAGCUTUA

AGGAGCUU

AAGGAGCU

UACUCAAG

UUUUACUC

CACCUUUU

AAAUUACA

GCAUAAAU

CUTUGCAUA

CCUUGCAU

ACCUTJGCA

UGGAGAAA

ACUGGAGA

AACUGGAG

CAACUGGA

CCCAACUG

UGAGUCCC

CUGAUGA X GAA AAAAGGAA CUGAUGA X GAA AUGAAAAG CUGAUGA X GAA AAUGAAAA CUGAUGA X GAA AAAUGAAA CUGAUGA X GAA AUCCCCAU CUGAUGA X GAA AAUCCCCA CUGAUGA X GAA AGUGGAAU CUGAUGA X GAA AUAGUGGA CUGAUGA X GAA AGAUAGUG CUGAUGA X GAA AGUGUGAG CUGAUGA X GAA AUUAGUGU CUGAUGA X GAA AUGCUCUU CUGAUGA X GAA AAUGCUCU CUGAUGA X GAA AUGCGCCA

S

55.5*.

S

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 CUGAUGA X GAA CUGAUGA X GAA CUGAUGA X GAA

AUAUGCGC

AAUAUGCG

AGUGCUUA

AAGUGCUU

AAAGUGCU

AGCUTUAAA

AGGAGCUU

ACUCAAGG

ACCACCUU

ACAUACCA

AUUACAUA

AAUUACAU

AAAUTUACA

ACCUUGCA

AUACCUUG

AAUACCULJ

UJUCCUUTUUC AUUUAAUG CUUTUUCAUU UAAUGGGG UtJUUCAUUU AAUGGGGA UUUCAUUUA AUGGGGAU AUGGGGAUU CC.ACUAUC UGGGGAUUC CACUAUCU AUUCCACUA UCUCACAC UCCACUAUC UCACACUA CACUAUCUC ACACUAAU CUCACACUA AUCUGAAA ACACUAAUC UGAAAGGA AAGAGCAUU AGCUGGCG AGAGCAUUA GCUGGCGC UGGCGCAUA UUAAGCAC GCGCAUALTU AAGCACU CGCAUAUTUA AGCACETLIJ UAAGCACUTU UAAGCUCC AAGCACUUU AAGCUCCU AGCACUUUA AGCUCCUU UUUAAGCUC CUUIGAGUA AAGCUCCUU- GAGUAAAA CCUUGAGUA AAAAGGUG AAGGUGGUA UGUAAUU UGGUAUGUA AUUUAUGC UAUGUAAUU UAUGCAAG AUGUAAUUU AUGCAAGG UGUAAUUUA UGCAAGGU UGCAAGGUA UUUICUCCA CAAGGUAUUE UCUCCAGU AAGGUAUULJ CUCCAGUU AGGUAUUUC UCCAGUUG GUAUUIUCUC CAGUTUGGG UCUCCAGUU GGGACUCA CUGAUGA X GAA AAAUACCU CUGAUGA X GAA AGAAAUAC CUGAUGA X GAA ACUGGAGA

S.

S S

OSS@

S

S

Se S S 0O55

C.

C

S.

C 0 5*55 *.eS

C

t5# We..

e Ce S SeSe

S

*OSe

S

CS SC OS

S

C

5573 5579 5581 5582 5585 5586 5596 5600 5615 10 5616 5617 5618 5626 5627 15 5634 5644 5661 5674 5688 20 5691 5693 5694 5700 5702 5708 5719 5724 5728 5737 5741 5742 5749 5751

AAUAUCCL

UtJAACUA-Z

CAUUAACL

tJCAUTUAAC

GGCUCAUJE

UGGCUCAUJ

CUIJCUAGU

JUUUcUtjc CAGUrJGAA

GCAGUUGA

AGCAGtJUG

AAGCAGUU

AAGUTUUCA

CAAGUUUC

CCCCAGGC

CAUGCUCA

UGUCUCCC

cccuUUcc

CUGAAGAG

ACCCUGAA

AGACCCUG

UAGACCCU

GAUCUUUA

UTJGAUCUU

GCCCACUU

AGCGAUCC

AGCUEJAGC

AGCCAGCU

AUCAAACA

UAGCAUCA

AUAGCAUC

UGCAUAAA

CUGCAUA

JCUGATJGA

LCUGAUGA

I 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 I CUGAUGA 2 CUGAUGA CUGAUGA

IGAA

GAA

GAA

GAA

GAA

GAP

GAP

GAA

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

AGUCCCAA

AUCCUGAG

AUAUCCUG

APUAUCCU

ACUAAUAU

APCUAPUA

AUGGCUCA

AGUGAUGG

AUGGGCUtJ

APUGGGCU

AAAUGGGC

AAAAUGGG

AGCAGTJUG

APGCAGUU

AGUUtJCAA

ACCCCAGG

AUUCCCAU

ACCCUGUC

AGGCGCCC

AGUAGGCG

AGAGUAGG

APGAGUAG

ACCCUGAA

AGACCCUG

AUCUTUUAG

AGGCCCAC

AUCCAAGG

AGCGAUCC

AGCCAGCU

ACAGAGCC

AACAGAGC

AGCAUCAA

AUAGCAUC

CUCAGGAUI

CAGGAUAUL

AGGAUAUUJP

AUAUUAGUL

UAUUAGtJTJ

UGAGCCAUC

CCAUCACUA

AAGCCCALU

AG CCCAUUJ

GCCCAUUJU

CCCAUULIUC

CAACUGCUU

APCUGCUUU

UJUGAAACUU

CCUGGGGUC

AUGGGAAUA

GACAGGGUA

GGGCGCCUA

CGCCUACUC

CCUACUCU

CUACUCUUC

UUCAGGGUC

CAGGGUCUA

CUAAAGAUC

GUGGGCCUU

CCIJUGGAUC

GGAUCGCUA

AGCUGGCTJC

GGCUCUGUU

GCUCUGUUU

ULJGAUGCUA

GAUGCUAUU

SUtJAGUTUAA

IAGUUAAUG

LGUTUAAUGA

rAAUGAGCC

,AUGAGCCA

ACUAGAAG

GAAGAPAA

UUCAACUG

UCAACUGC

CAACUGCU

APCUGCUU

UGAAACU

GAAACUTUG

GCCtJGGGG

UGAGCAUG

GGGAGACA

GGAAAGGG

CUCUJUCAG

UUCAGGGU

CAGGGUCU

AGGGTJCUA

UAAAGAUC

APGAUCAA

APGUGGGC

GGAUCGCU

GCUAAGCU

AGCUGGCU

UGUJUUGAU

UGAUGCUA

GAUGCUAU

UUAUGCA

UAUGCAAG

UUGGGACUC AGGAUAUU a 5752 5753 5761 5762 5767 5769 5773 5775 5776 5777 5788 5791 5793 5794 5800 5802 5808 5819 5824 20 5828 5837 5841 5842 5849 5851 5852 5853 5861 5862 5867 5869 5873 5875

ACUUGCAU

AACUTUGCA

UAGACCCU

AUAGAC CC

AAUACAUA

UAAAUACA

AUCCUAAA

GCAUCCUA

CGCAUCCU

GCGCAUCC

CUGAAGAG

ACCCUGAA

AGACCCUG

UAGACCCU

GAUCUUJA

UUGAUCUU

GCCCACUU

AGCGAUCC

AGCLTUAGC

AGCCAGCU

AUCAAACA

UAGCAUCA

AUAGCAUC

UGCAUAAA

CUUGCAUA

ACUTUGCAU

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 AAUAGCAU GAA AAAUAGCA GAA ACUUGCAU GAA AACUUGCA GAA ACCCUAAC GAA AGACCCUA GAA ACAUAGAC GAA AUACAUAG GAA AAUACAUA GAA AAAUACAU GAA AGGCGCAU GAA AGUAGGCG GAA AGAGUAGG GAA AAGAGUAG GAA ACCCUGAA GAA AGACCCUG GAA AUCUUUAG GAA AGGCCCAC GAA AUCCAAGG GAA AGCGAUCC GAA AGCCAGCU GAA ACAGAGCC GAA AACAGAGC GAA AGCAUCAA GAA AUAGCAUC GAA AAUAGCAU GAA AAAUAGCA GAA ACUJUGCAU GAA AACUUGCA GAA ACCCUAAC GAA AGACCCUA GAA ACAUAGAC GAA AUACAUAG

AUGCUAUUU

UGCUAUUUA

AUG CAAGUU

UGCAAGUUA

GUUAGGGUC

UAGGGUCUA

GUCUAUGUA

CUAUGUAUU

UAUGUAULU

AUGUAUUUA

AUG CGCCUA

CGCCUACUC

CCUACUCUU

CUACUCUUC

UUCAGGGUC

CAGGGUCUA

CUAAAGAUC

GUGGGCCUU

CCUTUGGAUC

GGAUCGCUA

AGCUGGCUC

GGCUCUGUU

GCUCUGUUU

UUGAUGCUA

GAUGCUAUU

AUG CUAUUU

UGCUAUUUA

AUG CAAGUU

UGCAAGUUA

GUUAGGGUC

UAGGGUCUA

GUCUAUGUA

CUAUGUALTJ

AUG CAAGU

UGCAAGUU

AGGGUCUA

GGGUCUAU

UAUGUAUU

UGUAUTUUA

UUUAGGAU

UAGGAUGC

AGGAUGCG

GGAUGCGC

CUCUTUCAG

UTUCAGGGU

CAGGGUCU

AGGGUCUA

UAAAGAUC

AAGAUCAA

AAGUGGGC

GGAUCGCU

GCUAAGCU

AGCUGGCU

UGUUUJGAU

UGAUGCUA

GAUGCUAU

UUUAUGCA

UAUGCAAG

AUG CAAGU

UGCAAGLU

AGGGUCUA

GGGUCUAU

UAUGUAUU

UGUAUUUA

UUUAGGAU

UAGGAUGU

5876 5877 5884 5892 5893 5904 5930 5937 5938 5940 5953 5958 5959 5962 15 5963 5964 5965 5967 5973 20 5976 5977 5978 5984 5996 5998 6002 6015 6021 6025 6026 6028 6029 GACAUC CT

AGACAUCC

AAGGUGC;

GGCUGCAC

UGGCUGCPA

CAGCUJUCTJ

GAAGCAGC

UCCCCAAG

CUCCCCAA

TJT.CUCCCC

AGGAAGCA

AUAAAAGG

GAUAAAAG

AUGGAUAA

CAUGGAUA

ACAUGGAU

UACAUGGA

AUUACAUG

AGLTUAAAU

UACAGUUA

CUACAGUU

UCUACAGU

UCAGGUTUC

GUtJACUUA

CGGUUACU

UCULJCGGU

CAGAGGCA

UAAGAACA

CACAUAAG

GCACAUAA

UGGCACAU

GUGGCACA

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

CUGAUGA

CUGAUGA I CUGAUGA2 CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA Y~ C GA1A

IGAA

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

GAUT

GAP

GAP~

GAP~

AAUACAUA

AAAUACAU

ACAUCCUA

AGGUGCAG

AAGGUGCA

ACUGGCUG

AUCCACUG

AGCAGCAA

AAGCAGCA

AGAAGCAG

ACUCUUCU

AGCAUACU

AAGCAUAC

AGGAAGCA

AAGGAAGC

AAAGGAAG

AAAAGGAA

AUAAAAGG

ACAUGGAU

AUUACAUG

AAUUACAU

AAAUUACA

ACAGUUAA

AGCUCAGG

AGAGCUCA

ACUUAGAG

ACAUUCUU

AGGCAUAC

ACAGAGGC

AACAGAGG

AGAACAGA

AAGAACAG

UAUGUAULTI

AUGUAUUJ

UAGGAUGUC

CUGCACCUI.

UGCACCUUC

CAGCCAGUC

CAGUGGAUL-

UUGCUGCULU

UGCUGCUUC

CUGCUUCUU

AGAAGAGUA

AGUAUGCUU

GUAUGCLTUC

UGCUUCCUU

GCTUCCULU

CUUCCTUUUu

UUCCUUUUA

CCUJUUUAUC

AUCCAUGUA

CAUGUAALU

AUGUAAUUU

UGUAAUtJUA

LJAACUGUA

CCUGAGCUC

UGAGCUCUA

CUCUAAGUA

AAGAAUGUA

GUAUGCCUC

GCCUCUGUU

CCUCUGUUC

UCUGUUCUU

CUGUTUCUTUA

J AGGAUGUC kGGAUGUCU

"UGCACCUU

J CUGCAGCC

UGCAGCCA

AGAAGCtTG rGCUGCUUC rCUTUGGGGA UtJGGGGAG

GGGGAGAA

UGCUUCCU

CCULTUUAU

CUUUUAUC

UUAUCCAU

UAUCCAUG

AUCCAUGU

UCCAUGUA

CAUGUAAU

AUUUAACU

UAACUGUA

AACUGUAG

ACUGUAGA

GAACCUGA

UAAGUAAC

AGUAACCG

ACCGAAGA

UGCCUCUG

UGUUCUUA

CU71AUGUG

UUAUGUGC

AUGUGCCA

UGUGCCAC

6040 UAAACAAG CUGAUGA X GAA AUGUGGCA

UCAACCUUU

UGCCACAUC CUUGUUUA o* 00 0 6043 6046 6047 6048 6055 6057 6061 6079 6082 6090 6091 6095 6104 6111 6124 6125 6126 6137 6141 6166 6169 6171 6181 6183 6187 6204 6226 6228 6229 6232 6235 6236 6239

CUUUAAAC

AGCCUUUI

GAGCCULTL

AGAGCCU.

CAUACAGP

LUCAUACP

UCUCUUCP.

GUGCUGAL

AAUGUGCJ

CACUAGGG

UCACtJAGG

AGGCUCAC

GGAGCCAG

GCUGCCAG

UUCCACAA

CLTUtCCACA

UCUUCCAC

UGGCUAGJ

CUtJCUGGC

GUGGAGAG

UUGGUGGA

UCUUGGUG

UGGAUUUA

UUUGGAUU

UUUGUULUG

UCUGGCUC

ACAACAAA

GAACAACA

GGAACAAC

AGAGGAAC

AGAAGAGG

AAGAAGAG

GUAAAGAA

CUGAUGA

CUGAUGA

JCUGAUGA

I CUGAUGA iCUGAUGA

LCUGAUGA

LCUGAUGA

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

*GAA AGGAUGUG 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 GPJA AGCCGCUG GAA AAGCCGCU GAA AAAGCCGC GAA AGUCUUCC GAA AGUGAGUC GAA ACUGUCCC GAA AGGACUGU GAA AGAGGACU GAA AUCUUGGU GAA AGAUCUUG GAA AUUUAGAU GAA AGCCUGCU GAA AUUUGUCC GAA AGAUUUGU GAA AAGAUUUG GAA ACAAAGAU GAA ACAACAAA GAA AACAACAA GAA AGGAACAA

CACAUCCU.

AUCCUUGUTL

UCCUUGUUL

CCUtJGLTUUP

UAAAGGCUC

AAGGCUCUC

CUCUCUGUA

GGGACCGUC

ACCGUCAUC

CAGCACALU

AGCACAUUC

CAUUCCCUA

GUGAGCCUA

UACUGGCUC

CAGCGGCUU

AGCGGCUUU

GCGGCUUUU

GGAAGACUC

GACUCACUA

GGGACAGUC

ACAGUCCUC

AGUCCUCUC

ACCAAGAUC

CAAGAUCUA

AUCUAAAUC

AGCAGGCUA

GGACAAAUC

ACAAAUCUU

CAAAUCUUrJ

AUCULUGUU

UUUGUTUGUU

UUGUTUGUUC

UUGUUCCUC

7 GUUUAAAG

TUAAAGGCU

FAAAGGCUC

,AAGGCUCU

UCUGUAUG

UGUAUGAA

UGAAGAGA

AUCAGCAC

AGCACAUU

CCCUAGUG

CCUAGUGA

GUGAGCCU

CUGGCUCC

CUGGCAGC

UTUGUGGAA

UGUGGAAG

GUGGAAGA

ACUAGCCA

GCCAGAAG

CUCUCCAC

UCCACCAA

CACCAAGA

UAAAUCCA

AAUCCAAA

CAAACAAA

GAG CCAGA

UTUUGUTUGU

UGUUTGUTUC

GUUJGLTUCC

GtJUCCUCU

CCUCUUCU

CUCUUTCUU

UUCUUJUAC

6241 GUGUAAAG CUGAUGA X GA;

S

6242 6244 6245 6246 6252 6280 6282.

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

UGUGUAA)

UAUGUGLU

GUAUGUGt

CGUAUGUC

GGLTUUTGCC

AUUUAUAP

GAUrUUAUP

UGAUUTUAL

CUGAUUUA

ACCUGAUU

AGUUACCU

CUUCCAGU

CUGAGUUU

UCUGAGU

t~UUUTJCU

AAUULGACU

AGAGAAUU

AAGUAGAG

AAAGUAGA

AAAAAGUA

AAAAAAAG

AAAAAAAA

AAAAAAA

AAAAAAAA

AAAAAAAA

AAAAAAAA

AAAAAAAA

AAAAAAAA

GAAAAAAA

GGAAAAAA

UGGAAAAA

k CUGAUGA kCUGAUGA J CUGAUGA

;CUGAUGA

;CUGAUGA

LCUGAUGA

6CUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I

CUGAUGA

CUGAUGA2 CUGAUGA2

CUGAUGA

GAP

GAP

GAA

GAA

GAA

GAA

GAP

GAP

GAP

GAP

GAP

GAP

GAA

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GAP

GA;

GA;

GAI

GA7

GA-Z

~AGAGGAPC

'APGAGGAA

'AGAAGAGG

APGAAGAG

SAAAGAAGA

AUGUGUAP

AUtJGCCAG AAPUUG CCA

AAAUUGCC

AAAAUUGC

AUAAAAUU

AUUUAUAA

ACCUGAUU

ACCUCCUU

AACCUCCU

AGUUTUAAC

AGGUCUUC

ACUGAGGU

AtJUGACUG

AAUUGACU

AGAAUUGA

AGAGAAUU

AGUAGAGA

AAGUAGAG

APAGUAGA

APAAGUAG

AAAAAGUA

AAAAAAGU

AAAAAAG

AAAAAAAA

AAAAAAAA

AAAAAAAA

GUUCCUCTY

UUCCUCUU(

CCUCUUCUJI

CUCUUCUMt UCUUCUUU)2

UUACACAUI

CUGGCAAUL

UGGCAAUUL

GGCAAUJUL

GCAAUUTUUP

AAUUUUAUP,

UUAUAAAUC

AAUCAGGUA

AAGGAGGUU

AGGAGGUUA

GUJUAAACUC

GAAGACCUC

ACCUCAGUC

CAGUCAAUU

AGUCAALTUC

UCAAUUCUC

APUUCUCUA

UCUCUACUU

CUCUACUU

UCUACULUU

CUACUUU

UACUUUUUU

ACUUUULtJ

CUUUUUUUU

UUUUUUUUU

uuuutUUu.nj

UUUUUUUUUI

LCLTUUACAC

UUUACACA

J UACACAUA J ACACAUAC k CACAUACG k. CGCAAACC

IULUAUAAAU

JUAUAAAUC

JAUAAAUCA

LUAAAUCAG

APUCAGGU

AGGUAACU

AACUGAG

AACUCAG

AGAAAAPA

AGUCAALU

APUUCUCU

CUCUACUU

UCUACULU

UACUULUIU

CUUUUJUU

uIUuUUUU

ULUUUU

UUUUUUUU

UUUUUUU

IJUULJUU

UUUtUUuUu

UUUUUUU

LUUUUTUC

UTUUUUUCC

LUULUUCCA

6357 UUGGAAAA CUGAUGA X GAP AAAAAPAAA UUUUUUUCA LTUUUUUUUU UI=CCAA

S

C

C

6358 6359 6360 6361 6362 6368 6373 6376 6388 6394 6401 6408 6409 6415 15 6416 6421 6423 6427 6428 20 6429 6433 6436 6437 6440 6441 6443 6444 6447 6450 6451 6461 6464

UUTJGGAAA

AUUUGGAA

GAULJUGGA

UGAUUUGG

CUGAUUUJTG

UAUUJAUCU

UGGGCUAU

UGCUGGGC

GUUAUCAC

UUlTJUUGU

UAAGGULU

GAACAGCU

UGAACAGC

AAGACAUG

CAAGACAU

GAAAUCAA

UTUGAAAUC

ALTUALTUGA

AAUtJALUG

UAAUULJ

GAALUAAU

UAAGAAUUt

UTJAAGAAU

UGAUUAAG

AUGAUEJAA

UAAUGAUU

UtJAAUGAU

CUCUUAAU

GGUCUCUU

UGGUCUCU

GUAUTJAU

GGAGUALU

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 AAAAAAAA GAA AAAAAAAA GAA AAAAAAAA GAA AAAAAAAA GAA AAAAAAA.A GAA AUUUGGAA GAA AUCUGAUU GAA AUTUAUCUG GAA AIJUUGCEJG GAA AUCACUAU GAA AUUtUGUUA GAA AGGUUUUA GAA AAGGUUUU GAA ACAGCUAA GAA AACAGCUA GAA ACAUGAAC GAA AGACAUGA GAA AUCAAGAC GAA AAUCAAGA GAA AAAUCAAG GAA AUTUGAAAU GAA AIJUAUULGA GAA AAUUAUUG GAA AUUAAUTUA GAA AAUUAAUU GAA AGAAUUAA GAA AAGAAUUIA GAA AUUAAGAA GAA AUGAUUAA GAA AAUGAUUA GAA AUGGUCUC GAA AUUAUGGU UUUUIJUUUU UTUUCCAAA UtJUUUUUUU UIJCCAAAU UUUUUUUJLU UCCAAAUC UUUUUUUUU CCAAAUCA UUUUUUTJUC CAAAUCAG UUCCAAAtJC AGAUAAUA AAUCAGAUA AUAGCCCA CAGAUAAUA GCCCAGCA CAGCAAAUA GUGAUAAC AUAGUGAUA ACAAAUAA UAACAAAUA AAACCUUA UAAAACCUU AGCUGUTUC AAAACCUUA GCUGUTUCA UUAGCUGUU CAUGUCUU UAGCtJGUtJC AUGUCUUG GUUCAUGUC UUGAUUUC UCAUGUCUU GAUUTUCAA GUCUUTGAUTU UCAAUAAU UCUUGAUUU CAAUAAUU CIJUGAUUUC AAUAAUUA AUUUCAAUA AUUAAUUTC UCAAUAAUU AAUEJC=UA CAAUAAUTUA AUTUCUTUAA UAAUUAATJU CUUAAUCA AAUUAAUUC UTUAAUCAU UUAAUUCUU AAUCAUUA UAAUUCUUA AUCAUUAA UTUCUUAAUC AUTUAAGAG UUAAUCAUU AAGAGACC UAAUCAUUA AGAGACCA GAGACCAUA AUAAAUAC ACCAUAAUA AAUACUCC UAAUAAAUA CUCCUUU 6468 AAAAGGAG CUGAUGA X GAA AUUUAUUIA 6471 UUGAAAAG CUGAUGA X GAA AGUAUULJA 6474 6475 6476 6477 6497 6498 6503 6506 6507 6510 6515 6518 6519 6525 6530 6531 6534 6539 6547 6551 6555 6559 6570 6571 6575 6582 6584 6585 6590 6609 6612 6615

CUCUUGA

UCUCUUG,

UTUCUCU

UUUCcUcui

ACAAUTUCI

AACAALU(

UGAGUAA(

AGCUGAGI

GAGCUGAC

AAGGAGC.

GULUGAAC

UGAGULUG

CUGAGUUU

ACAAACCU

AUGCUACA

UAUGCUAC

AUGUAUGC

GACUCAUG

GAUGGAUG

GACUGAUG

CUUTUGACU

CAULJCUUU

CCAGAUGG

UCCAGAUG

AGACUCCA

UACAUTUAA

UCUACAUJ

UTUCUACAU

UUCUTUc

AUUAUUAC

CUCAUJUAU

UAGCUCAU

P, CUGAUGA k. CUGAUGA

CUGAUGA

J CUGAUGA J CUGAUGA

CUGAUGA.

CUGAUGA

JCUGAUGA

;CUGAUGA:

T CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA2

CUGAUGA)

CUGAUGA)

CUGAUGA

CUGAUGA Y~ CUGAUGA Y CUGAUGA Y 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 GAA AGGAGUAU X GAA AAGGAGUA K GAA AAAGGAGU K GAA AAAAGGAG K GAA AUGGUUU C GAA AAUGGUUU C GAA AUUCUAAU C GAA ACAAUUCU [GAA AACAAUUC GAA AGUAACAA GAA AGCUGAGU GAA AGGAGCUG GAA AAGGAGCU GAA AGLUJUGAA GAA ACCUGAGU GAA AACCUGAG GAA ACAAACCU GAA AUG CUACA GAA ACUCAUGU GAA AUGGACUC GAA AUGGAUGG GAA ACUGAUGG GAA ACCAUUCU GAA AACCAUUC GAA AUGGAACC GAA ACUCCAGA GAA AGACUCCA GAA AAGACUCC GAA ACAUUtAAG GAA AGUCUCCA GAA ACAAGUCU GAA AUUACAAG UAAAUACUC

CUUUTUCAA'

AUACUCCUU

UUCAAGAG

UACUCCUTUU

UCAAGAGA

ACUCCUUUU CAAGAGAA CUCCUUUUC

AAGAGAAA

AAAACCAUU AGAAUUGu AAACCAUUA

GAAUUGUU

AUUAGAAUEJ GUUACUCA AGAAUUGUU

ACUCAGCU

GAAUUGUUA

CUCAGCUC

UUGUUACUC AGCUCCUU ACUCAGCUC

CTJUCAAAC

CAGCUCCUU CAAACUCA AGCUCCUUC

AAACUCAG

LUtCAAACUC

AGGUUUGU

ACUCAGGUU UGUAGCAU CUCAGGUUU GUAGCAUA AGGtJUUGUA

GCAUACAU

UGUAGCAUA CAUGAGUC ACAUGAGUC CAUCCAUC GAGUCCAUC CAUCAGUC CCAUCCAUC

AGUCAAAG

CCAUCAGUC

AAAGAAUG

AGAAUGGUU

CCAUCUGG

GAAUGGUTUC CAUCUGGA GGUUCCAUC UGGAGUCU UCUGGAGUC

UTUAAUGUA

UGGAGUCUTU AAUGUAGA GGAGUCUUA AUGUAGAA CUUAAUGUA

GAAAGAAA

UGGAGACUU

GUAAUAAU

AGACUUGUA

AUAAUGAG

CUUGUAAUA AUGAGCUA

S

*S5555

S

6623 6626 6627 6637 6640 6641 6644 6645 6650 6662 6674 6675 6682 6685 6687 6688 6693 6696 6697 20 6703 6704 6705 6719 6726 6743 6744 6747 6748 6749 6755 6756 6757 6764 UILUGtAAC

CACUUUGU

GCACUUUG

UAAUGAAC

UUUILJAAUG

AUUUTUAAU

GCUAUUUUU

UGCUAUUU

UTUCAGUGC

CAUGUUTUC

UAUCAGUU

IJUAUCAGU

UGGAAUAU

GAUtJGGAA AUGAUUtGG

AATJGAUUG

UGGCAAAU

AAAUGGCA

UAAAUGGC

UIJGUCAUA

IUUGUCAU

UUUUGUCA

UUAGUG CC

UUCUULJGU

CUGAAAGG

UCUGAAAG

AACUCUGA

AAACJCIG

GAAACUCU

AUCUCAGA

UAUCUCAG

UTUAUCUCA

ACGUACAU

*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 AGCUCAUU GAA ACUAGCUC GAA AACUAGCU GAA AGCACUUJ GAA ACAAGCAC GAA AACAAGCA GAA AUGAACAA GAA AAUGAACA GAA AUUUUAAU GAA AUUELJUCAG GAA AUUJCAUGU GAA AAUUCAUG GAA AUCAGUUA GAA AUTUAUCAG GAA AUAUTUAUC GAA AAUAUUAU GAA AUUGGAAU GAA AUGAUUJGG GAA AAUGAUTUG 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

AAUGAGCUA

GAG CUAGUU

AGCUAGUUA

AAAGUGCUU

GUGCUUGtU

UGCUUGUUC

UUGUUCAUU

UGUUCAUUA

AUUAAAAUA

CUGAAAAUU

ACAUGAAUU

CAUGAAUUA

UAACUGAUA

CUGAUAAUA

GAUAAUAUU

AUAAUAUUC

AUUCCAAUC

CCAAUCAUU

CAAUCAUUUJ

UUUGCCAUU

IJUGCCALUU

UGCCAUUUA

AAAAUGGUU

tJUGGCACUA

CGAGCACUU

GAGCACUUC

CACUUCCLTUJ

ACUUCCUTU

CUUCCUTUUC

UTUCAGAGLU

UCAGAGULTU

CAGAGULUC

UCUGAGAUA

*GUUACAAA

ACAAAGUG

CAAAGUGC

GUUCAUUA

CAUUAAAA

AUUAAAAU

AAAAUAGC

AAAUAGCA

GCACUGAA

GAAACAUG

AACUGAUA

ACUGAUAA

AUAUUCCA

UUCCAAUC

CCAAUCAU

CAAUCAUU

AUUUGCCA

UGCCAUUU

GCCAUUUA

UAUGACAA

AUGACAAA

UGACAAAA

GGCACUAA

ACAAAGAA

CCUtJUCAG

CUUUCAGA

UCAGAGUU

CAGAGUUU

AGAGUUTUC

UCUGAGAU

CUGAGAUA

UGAGAUAA

AUGUACGU

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

UCCACCCI

AAGACACI

ACUGACA7

GGACUGAC

CUUTGGACI.

ACUUCtUUG

CUAAAAU

CCUAAAAU

GUCCCUAA

GGUCCCUA

GGGUCCCU

CGGGUCCC

UAGGAAAC

GGCUAGGA

GGGCUAGG

UGGGCUAG

tJUGUGGGC

AUCUGUUU

CUAGCGAG

AGGCUAGC

AAUGAGGC

AUUTUAAAU

UCAAUUUTA

AtJCAAULU

AAUCAAUU

CLUUAAUC

cuCCuUt

UCCUCCLTU

CGGCCAAA

GUCGGCCA

UGUCGGCC

3 CUGAIJGA k. CUGAUGA k CUGAUGA

CUGAUGA

CUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA,

CUGAUGA

CUGAUGA:

CUGAUTGA I

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA I

CUGAUGA

CUGAUGA 2 CUGAUGA 2 CUGAUGA 2 CUGAUGA Y~ X GAA ACAUUAUC K GAA ACUGUUCC KC GAA ACUUGCAC K GAA ACACAGAC GAA AGACACAG CGAA ACAAGACA C GAA ACUGACAA C GAA ACAUCUCG GAA AACAUCUC GAA ALUUAACAU GAA AAUUAACA GAA AAAUUAAC GAA AAAAUTUAA GAA AGGCACGG GAA ACAAGGCA GAA AACAAGGC GAA AAACAAGG GAA AGGAAACA GAA AUGUUUGC GAA AUCUGUU GAA AGUAUCUG GAA AGCGAGUA GAA AGGCUAGC GAA AUGAGGCU GAA AAUGAGGC GAA AAAUGAGG GAA AUILJUAAAU GAA AUCAAULU GAA AAUCAALU GAA AUGCACUC GAA AGAUGCAC GAA AAGAUGCA GAUAAUGUj

GGAACAGU(

GUGCAAGU(

GUCUGUGUC

CUGUGUCMt

UGUCUUGUC

UUGUCAGUC

CGAGAUGUt GAGAUGUU~z

AUGUUAAUL

UGUUAAUUU:

GUUAALUUU

UUAAUUUUA

CCGUGCCUU

UGCCtJUGUU

GCCUUGUUUL

CCUUGUUUIC

UGTUUCCUA

GCAAACAUC

AAACAGAUA

CAGAUACUC

UACUCGCUA

GCUAGCCUC

AGCCUCALU

GCCUCAUUU

CCUCAUUUA

AUUUAAAUU

AAAUUGAUU

AAUUJGAUUA

GAGUGCAUC

GUGCAUCLU

UGCAUCLUU

k. CGUGGAAC

UGGGUGGA

UGUGUCUU

:UUGUCAGU

J GUCAGUCC

AGUCCAAG

CAAGAAGU

JAAUUUUAG

AUUUUAGG

UtJAGGGAC

UAGGGACC

AGGGACCC

GGGACCCG

GUtJUCCUA

UCCUAGCC

CCUAG CCC

CUAGCCCA

GCCCACAA

AAACAGAU

CUCGCUAG

GCUAGCCU

GCCUCAUU

AUUUAAAU

UAAAUUGA

AAAUUGAU

AAUUGAUU

GAUUAAAG

AAAGGAGG

AAGGAGGA

UUUGGCCG

UGGCCGAC

GGCCGACA

6970 CACACAGU CUGAUGA X GAA ACACCACU AGUGGUGUA ACUGUGUG a.

a. a a 7026 7034 7035 7036 7043 7047 7049 7050 7051 7065 7066 7067 7068 7073 7074 7077 7078 7079 7080 7082 7095 7097 7102 7108 7110 7124 7125 7129 7132 7134 7136 7137 7138 AACACACA CUGAUGA X GAA ACACCCAC AUGCACAA CUGAUGA X GAA ACACACAU UAUGCACA CUGAUGA X GAA AACACACA UUAUGCAC CUGAUGA X GAA AAACACAC UAAAUAGU CUGAUGA X GAA AUJGCACAA UCCUUAAA CUGAUGA X GAA AGUUAUGC tJTJICCUUA CUGAUGA X GAA AUAGUUAU GUTUUCCUTU CUGAUGA X GAA AAUAGUTUA AGUULUCCU CUGAUGA X GAA AAAUAGLU AACUUUAA CUGAUGA X GAA AUUCCAGU UAACUEJUA CUGAUGA X GAA AAtJUCCAG GUAACUULJ CUGAUGA X GAA AAAUUCCA AGUAACULJ CUGAUGA X GAA AAAAUUCC AUAAAAGU CUGAUGA X GAA ACUUUAAA UAUAAAAG CUGAUGA X GAA AACUtJUAA UUGUAUAA CUGAUGA X GAA AGUAACUU UUUGUAUA CUGAUGA X GAA AAGUAACU GUULUGUAU CUGAUGA X GAA AAAGUAAC GGUUTUGUA CUGAUGA X GAA AAAAGUAA UUGGUUUG CUGAUGA X GAA AUAAAAGU GUAGCAUA CUGAUGA X GAA AUUCUUGG CUGUAGCA CUGAUGA X GAA AUAUUCUU UAUAUCUG CUGAUGA X GAA AGCAUAUA CUGUCUrJA CUGAUGA X GAA AUCUGUAG GUCUGUCU CUGAUGA X GAA AUAUCUGU UAGGACCA CUGAUGA X GAA ACCAUGUC AUAGGACC CUGAUGA X GAA AACCAUGU AAAUAUAG CUGAUGA X GAA ACCAAACC UAGAAAUA CUGAUGA X GAA AGGACCAA ACUAGAAA CUGAUGA X GAA AUAGGACC UGACUAGA CUGAUGA X GAA AUAUAGGA AUGACUAG CUGAUGA X GAA AAUAUAGG CAUGACUA CUGAUGA X GAA AAAUAUAG GUGGGUGUA UGUGUGUU* AUGUGUGUU UUGUGCAU UGUGUGUUU UGUGCAUA GUGUGUUtJU GUGCAUAA UUGUG CAUA ACUAUU-UA GCAUAACUA UUUAAGGA AUAACUAUU UAAGGAAA UAACUAUULU AAGGAAAC AACUAUUTJA AGGAAACU ACUGGAAUU UtJAAAGU CUGGAAUUU UAAAGUUA UGGAAUUEJU AAAGUTUAC GGAAUUUUA AAGUtJACU UWLAAAGtJU ACUUUUAU UUAAAGtJUA CUUUUAUA AAGUUACUU UUAUACAA AGUUACUUU UAUACAAA GUUACUUUU AUACAAAC UTUACULTUUA UACAAACC ACUUUULAUA CAAACCAA CCAAGAAUA UAUGCUAC AAGAAUAUA UGCUACAG UAUAUGCUA CAGATJAUA CUACAGAUA UAAGACAG ACAGAUAUA AGACAGAC GACAUGGUU UGGUCCUA ACAUGGUUU GGUCCUAU GGUtJUGGUC CUAUALUU UUGGUCCUA UAUUUCUA GGUCCUAUA UTUUCUAGU UCCUAUAUU UCUAGUCA CCUAUAUUU

CUAGUCAU

CUAUAUUUC UAGUCAUG 7140 7143 7155 7157 7158 7159 7162 7164 7169 10 7171 7172 7175 7177 7180 7182 7185 7186 7192 7194 20 7195 7196 7198 7199 7202 7208 7209 7212 7215 7218 7225 7226 7229 7233 AUCAUGAC CUGAUGA X UUCAUCAU CUGAUGA X AUACAAAA CUGAUGA X GUAUACAA CUGAUGA X GGUAUACA CUGAUGA X UGGUAUAC CUGAUGA X AGAUGGUA CUGAUGA X GAAGAUGG CUGAUGA X UAUAUGAA CUGAUGA X AUTUAUAUG CUGAUGA X UATJUAUAU CUGAUGA X 9 4*4

GUAUALUA

AAGUAUAU

UUUAAGUA

UUUUUAAG

AUAUUUUU

AAUAUUUJ

UUAAGAAA

AAUUAAGA

CAAUTUAAG

CCAAUTUAA

UCCCAAUU

AUCCCAAU

CAAAUCCC

CGAUTUACA

ACGAUUTAC

GGUACGAU

GUtJGGUAC

UAAGUUGG

UAUCAAUU

UUAUCAAU

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 AGAAAUAU GAA ACUAGAAA GAA ACAUUCAU GAA AUACAUUC GAA AAUACAUU GAA AAAUACAU GAA ACAAAAUA GAA AUACAAAA GAA AUGGUAUA GAA AGAUGGUA GAA AAGAUGGU GAA AUGAAGAU GAA AUAUGAAG GAA ALJUAUAUG GAA AUAUUAUA GAA AGUAUAUU G.AA AAGUAUAU GAA AUTUUUUAA GAA AUAUtUtJ GAA AAUAUUUU GAA AAAUAUUU GAA AGAAAUAU GAA AAGAAAUA GAA AUUAAGAA GAA AUCCCAAU GAA AAUCCCAA GAA ACAAAUCC GAA AUIJACAAA AUAUtJUCUA GUCAUGAU UUUCUAGUC AUGAUGAA AUGAAUGUA tUUTJGUAU GAAUGUAUU UUGUAUAC AAUGUAUUU UGUAUACC AUGUAUUUU GUAUACCA UAUUUUGUA UACCAUCU ULUJUGUAUA CCAUCUUC UAUACCAUC UUCAUAUA UACCAUCUU CAUAUAAU ACCAUCUUC AUAUAAUA AUCUTUCAUA UAAUAUAC CUUCAUAUA AUAUACUU CAUAUAAUA UACUUAAA UAUAAUAUA CUUAAAAA AAUAUACUTU AAAAAUAU AUAUACUTUA AAAAUALU UUAAAAAUA UUUCUUAA AAAAAUAUU UCUUAAUU AAAAUAJUU CUUAAUTUG AAAUAUUUC UUAAUUTGG AUAUUUTCUU AAUUGGGA UAUIJUCUUA AUUGGGAU UUCUtJAAUU GGGAUUUG AUUGGGAUU UGUAAUCG TJUGGGAUUU GUAAUCGU GGAUUUGUA AUCGUACC UUUtGUAAUC GUACCAAC GUAAUCGUA CCAACUUA UACCAACUU AAUUGAUA ACCAACUUA AUUGAUAA AACUUAAUUI GAUAAACU UAAUUGAUA AACUUGGC CUGAUGA X GAA ACGAUTUAC CUGAUGA X GAA AGUUGGUA CUGAUGA X GAA AAGUUGGU AGUTUUAUC CUGAUGA X GAA AUUAAGUU GCCAAGUEJ CUGAUGA X GAA AUCAAUUA

S

0555

S

S.

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

CAGUUGCC

GAACAUAA

AGAACAUA

CAGAACAU

ACAGAACA

GGAGACAG

AGGAGACA

UGGAAGGA

UAUGGAAG

AUULTAUGG

AAUUUAUG

GAAAAAUU

UTJUUGAAA

AUEJUUGAA

UAUUtUUGA

GUAUUUTUG

AGUAUUUU

UGAAUTUAG

UGUUIGAAU

CLTUUGUtJG UCUUGtU I

AAAAAAAA

GGAAAAAA

AGGAAAAA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA

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 GAA AGIJUUAUC GAA AGCAGUUG GAA AAGCAGUU .K GAA AAAGCAGU GAA AAAAGCAG C GAA ACAUAAAA CGAA AACAUAAA CGAA ACAGAACA GAA AGACAGAA GAA AGGAGACA GAA AAGGAGAC GAA AUGGAAGG GAA AUtJUAUGG GAA AAUTUUAUG GAA AAAtJUUAU GAA AAAAUTUUA GAA AAAAAUUU GAA AUUTUUGAA GAA AGUAUUUU GAA AUUAGUAU GAA AAUTUAGUA GAA AGCLUUUU GAA AGAGCUUU GAA AAGAGCUU GAA AAAGAGCU GAA AAAAGAGC GAA AAAAAGAG GAA AAAAAAGA GAA AAAAAAAG GAA AAAAAAAA GAA AGGAAAAA GAA AUUUUAGG GAA AGUUUAUU GAUAAACUU GGCAACUG CAACUGCUU UUAUGUUJC AACUGCUUU

UAUGUUCU

ACUGCUUUU

AUGUUCUG

CUGCUUUUA UGUUCUGU UUUUAUGUU CUGUCUCC UUUAUGUUC UGUCUCCU UGUEJCUGUC UCCUUCCA UUCUGUCUC CUUCCAUA UGUCUCCUU CCAUAAAU GUCUCCUUC CAUAAAUU CCUUCCAUA AAUUtJUUC CCAUAAAUU UTUUCAAAA CAUAAAUUU UTUCAAAAU AUAAAUTLJ UCAAAAUA UAAAUTUUU CAAAAUAC AAAUUJUC AAAAUACU UTUCAAAAUA CUAAUUCA AAAAUACUA AUUCAACA AUACUAAUU CAACAAAG UACUAAUUC AACAAAGA AAAAAGCUC ULUUUUUU AAAGCUCUIJ UTUUULUCC AAGCUCUUU UUUUUCCU AGCUCUUUU UUUUCCUA GCUCUUUtJU UUIJCCUAA CUCUUUUUTU UUCCtJAAA UCUUUUUU UCCUAAAA CUUUUUUUU CCUAAAAU UUUUUUtUUC CUAAAAUA UUUUTUCCUA

AAAUAAAC

CCUAAAAUA

AACUCAAA

AAUAAACUC AAAUULJAU UAGGAAAA CUGAUGA X UUAGGAAA CUGAUGA X UUUAGGAA CUGAUGA X UUUUAGGA CUGAUGA X AUUTUUAGG CUGAUGA X UAUUUTUAG CUGAUGA X GUUUAUUU CUGAUGA X UUUGAGIJU CUGAUGA X AUAAAUUTU CUGAUGA X Ge Co 0

S

C@

C

0**e

SC

C C C Ce

C

Ce. C *.eC

S

0500 Ce'.

0

S.C.

7335 7336 7337 7339 7342 7345 7346 7347 7362 10 7363 7373 7374 7383 7385 15 7393 7397 7401 7403 74-0 4 7405 7406 7418 7424 7425 7428 7429 7430 7437 7440 7447 7448 7449

CAAGGAUA

ACAAGGAU

AACAAGGA

UAAACAAG

CUCUAAAC

CUGCUCUA

UCUGCUCU

CUCUGCUC

UGJUUcTU CCAtJUCA

ACCAUUUC

UUUtJUGA

AAUUUUUU

UAUUUAGC

AAAAUAUU

AUUGAAAA

CCAtJUGAA

UCCAUUGA

UUCCAUUG

UUIJCCAUU

CUAACAUU

GCUAAACU

AGCUAAAC

AUCAGCUA.

AAUCAGCU

CAAUCAGC

CCCCAUAC

AAACCCCA4

GGUUCGA

AAGGUCG

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 X4 CUGAUGA X CUGAUGA X GAA AUUUGAGU GAA AAUUUGAG GAA AAAUULUGA GAA AUAAAUUU GAA AGGAtJAAA GAA ACAAGGAU GAA AACAAGGA GAA AAACAAGG GAA AUTUUUUCU GAA AALUJUUTUC GAA AGUUUUUC GAA AAGJUUUU GAA ACCAUTUUC GAA AGACCAUU GAA AUUUUUTUG GAA AGCAAUUUJ GAA AUUUAGCA GAA AUAUUUAG GAA AAUAUUUA GAA APLAUAUJUU GAA AAAAUAUU GAA AGUUUUCC GAA ACAUUTUAG GAA AACAUTUUA GAA ACUAACAU GAA AACUAACA GAA AAACUAAC GAA AUCAGCUA GAA ACAAUCAG GAA ACCCCAUA GAA AACCCCAU GAA AAACCCCA ACUCAAAUTU UAUCCUUG CUCAAAUULU AUCCIJUGU UCAAAtJUUA UCCUUGUU AAAULUAUC CUUGUUUA ULJUAUCCUU GtUtJAGAG AUCCUUGUU UAGAGCAG UCCUULGUUU AGAGCAGA CCUUGUUUA GAGCAGAG AGAAAAAUU AAGAAAAA GAAAAAUTUA AGAAAAAC GAAAAACUTJ UGAAAtJGG AAAAACUUEJ GAAAUGGU GAAAUGGUC UCAAAAAA AAUGGUCUC AAAAAAUU CAAAAAAUTU GCUAAAUA AAAUUGCUA AAUAULTUIJ UGCUAAAUA UUUUCAAU CUAAAUAUUI UTUCAAUGG UAAAUAUUUJT UCAAUGGA AAAUAUUUU CAAUGGAA AAUAUUUUC AAUGGAAA GGAAAACUA AAUGLTUAG CUAAAUGUU AGUUUAGC UAAAUGUUA GUTUUAGCU AUGUUAGUU UAGCUGAU UGUUAGUUJ AGCUGAUU GLTUAGUUtJA GCUGAIJUG UAGCUGAUU GUAUGGGG CUGAUUGUA UGGGGUUU UAUGGGGUU UUCGAACC AUGGGGUUU UCGAACCU UGGGGUUUU CGAACCUU GGGGUUUUC GAACCUUU 7450 AAAGGUUC CUGAUGA X GAA AAAACCCC .0.

.0 0 0 7457 7458 7459 7463 7464 7465 7466 7469 7470 7473 7474 7475 7476 7480 15 7482 7483 7484 7495 7499 7506 7509 7510 7515 7531 7532 7534 7541 7545 7547 7549 7550 7557

AAAAGUG

AAAAAGU(

CAAAAAGI

CAAACAAj ACAAACA2

AACAAACI

AAACAAAC

GUAAAACI

GGUAAAAC

AUAGGUA-Z

AAUAGGUA

AAAUAGGE

GAAAUAGG

UTUGUGAAA

AGUUGUGA

CAGUUGUG

ACAGUUGU

UGGCAAUU

UUALUJGGC

ACAGGAAU

UGGACAGG

AUGGACAG

UUUTJCAUG

CACUGGAU

ACACUGGA

CUACACUG

AAUAUAUC

GUCAAAUA

UGGtJCAAA

GAUGGUCA

UGAUGGUC

CAUAGGGU

Pi CUGAUGA

CUGAUGA

J CUGAUGA

CUGAUGA

k CUGAUGA k. CUGAUGA 7CUGAUGA

SCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2

CUGAUGA)

CUGAUGA

CUGAUGA 2 CUGAUGA Y~ CUGAUGA Y CUGAUGA Y CUGAUGA X X GAA AGGLJCGA X GAA AAGGUtJCG KC GAA AAAGGUUC K GAA AGUGAAAG .K GAA AAGUGAAA C GAA AAAGUGAA C GAA AAAAGUGA C GAA ACAAAAAG r GAA AACAAAAA GAA ACAAACAA GAA AACAAACA GAA AAACAAAC GAA AAAACAAA GAA AGGUAAAA GAA AUAGGUAA GAA AAUAGGUA GAA AAAUAGGU GAA ACACAGUU GAA AtJUUACAC GAA AUUJGGCAA GAA AUUAUTUGG GAA AAUUAUTUG GAA ACAGGAAU GAA AUUUGCAU GAA AAUUUGCA GAA AUAAUTUUG GAA ACACUGGA GAA AUCUACAC GAA AUAUCUAC GAA AUAUAUCU GAA AAUAUAUC GAA AUGGUCAA

UCG.AACCU

CGAACCUTJ

GAACCUUUIP

CUUUCACU1I

UUUCACUUI

UUCACUULTR

UCACUJUUTI

CUUUTJUGUI

UUJUGULR

IJUGUUUGUL

UGUUUGUUL

GUUUGUTUUL

UTUUGUUUUP

UULUUACCUA

UUACCUAUU)

UACCUAUUU

ACCUAUUUC

AACUGUGUA

GUGUAAAUU

UTUGCCAAUA

CCAAUAAUUJ

CAAUAAUUC

AUTUCCUGUC

AUG CAAAUU

UGCAAAU-UA

CAAAUUAUC

UCCAGUGUA

GUGUAGAUA

GUAGAUAUA

AGAUAUAUU

GAUAUAUUU

UUGACCAUC

U UCACUUUUT UI CACUUUUU C ACUUUUUG J UTUUGUUUG J UUGtJUUGU J UGULTJGUU J GUUUGLUUJ J UGUUUUAC

JGUUUUACC

J UUACCUAU J UACCUAUU

TACCUAUUU

CCUAUULUC

*UUUCACAA

UCACAACU

CACAACUG

ACAACUGU

AAUEJGCCA

GCCAAUAA

AUUCCUGU

CCUGUCCA

CUGUCCAU

CAUGAAAA

AUCCAGUG

UCCAGUGU

CAGUGUAG

GAUAUAUU

UALUUJGAC

UUUGACCA

UGACCAUC

GACCAUCA

ACCCUAUG

7563 AAUAUCCA CUGAUGA X GAA AGGGUGAU AUCACCCUA UGGAUAIJ 7569 CUAGCCAA CUGAUGA X GAA AUCCAUAG a a a a.

a *aaa..

a 7571 7576 7579 7580 7581 7586 7587 7588 7590 7591 7599 7600 7603 7604 7605 7617 7623 7625 20 7627 7629 7630 7632 7637 7639 7640 7643 7645 7646 7648 7651 7652 AACUAGC C

GGCAAAAC

AAAGGCAA

UAAAGGCA

AUAAAGGC

GCUUJAAUA

UGCUUAAU

UEJGCUUAA

AUUJGCU

AAUTUUGCU

CUGAAAUG

GCUGAAAU

CAGGCUGA

UCAGGCUG

UUCAGGCU

UAUAGGCA

AGAAUAUA

AGAGAAUA

GCAGAGAA

GAGCAGAG

AGAGCAGA

AAAGAGCA

AAUACAAA

AGAAUACA

GAGAAUAC

AAGGAGAA

CAAAGGAG

UCAAAGGA

GUEJCAAAG C

CGGGUUCAC

ACGGGUUCC

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 7UGAUGA X ZUGAUGA X 7UGAUGA X :UGAUGA X 'UGAUGA X ~UGAUGA X 'UGAUGA XC .TGAUGA XC CUGAUGA X GAA AUAUCCAU GAA AGCCAAUA GAA ACUAGCCA GAA AACUAGCC GAA AAACUAGC GAA AGGCAAAA GAA AAGGCAAA GAA AAAGGCAA GAA AUAAAGGC GAA AAUAAAGG GAA AUtJGCUU GAA AAUUUGCU GAA AUGAAUUU GAA AAUGAALJU GAA AAAUGAAU GAA ACAUUCAG GAA AGGCAGAC GAA AUAGGCAG GAA AUAUAGGC GAA AUAUAUAG GAA AAUAUAUA GAA AGAAUAUA GAA AGCAGAGA GAA AGAGCAGA GAA AAGAGCAG GAA ACAAAGAG 3AA AUACAAAG 7AA AAUACAAA 7AA AGAAUACA 3AA AGGAGAAU -AA AAGGAGAA CUAUGGAUA UUGGCUAG AUGGAUAUU GGCUAGUU UAUUGGCUA

GUUUUGCC

UGGCUAGUU

UUGCCUJUU

GGCUAGUTUU UGCCtJUUA GCUAGUJUU GCCIJUUAU UtJUUGCCtJU UAUUAAGC UUUGCCUUU AUUAAGCA UUGCCUUUA UUTAAGCAA GCCUUUAUIJ AAGCAAAU CCUUUAUTUA AGCAAAUUI AAGCAAAUU CAUUUCAG AGCAAAUUC

AUUUCAGC

AAAUJICAUU UCAGCCUG AAUUCAUTUU CAGCCUGA AUUCAUTUUC AGCCUGAA CUGAAUGUC UGCCUAUA GUCUGCCUA

UAUAUUCU

CUGCCUAUA UAUUCUCU GCCUAUAUA UUCUCUGC CUAUAUAUU CUCUGCUC UAUAUAUJC UCUGCUCU UAUAUUCUC UGCUCUU UCUCUGCUC UUUGUAUU UCUGCUCUU

UGUAUUCU

CUGCUCUUU

GUAUUCUC

CUCUUUGUA UUCUCCUU CUUUGUAUU CUCCUUUG UUUGUAUUC UCCUUUGA UGUAUUCUC

CUUUGAAC

AUTUCUCCUTU

UGAACCCG

UUCUCCUUU GAACCCGU GAACCCGUU AAAACAUC 7661 GAUGUUUU CUGAUGA X GAA ACGGGUUC 7 66 2 GGAUGUUTU CUGAUGA X GAA AACGGGUU AACCCGUUtA AAACAUCC 7669 UGCCACAG CUGAUGA X GAA AUGUUUUA UAAAACAUC CUGUGGCA 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 a2 base-pairs.

i 0 91 Table III: Human fltl VEGF Receptor-Hairpin Ribozvme and Substrate Sequence nt.

Position HP Ribozyme Sequence Substrate 16 39 180 190 278 290 295 298 302 420 486 537 565 721 786 863 CCCGGAGG AGAA GAGAGO ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

CCGCUCCG

CCGCCAGA

AACGACCC

GCGCGCAC

GACAGCUG

AAGCAGAC

GAGAAGCA

CUGUGAGA

CAUTJUAUG

CUUCCACA

UUUGCUUG

AUAUUUGC

CGUAACCC

CGUUUUCC

CUUCACAG

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCCGCC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GUCCUC ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA GCCAGA ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GGACCC ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA GCGCGC ACCAGAGAA.ACACACGUUGUGGUACAUUACCUGGUA GAGCAG ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GCUGAG ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GACAGC ACCAGAGAAACACA.CGUIJGUGGUACAUUACCUGGUA GCUUCC ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA GAIJUUA ACAAAAAAGUGGUCUACGU GUGUUC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GUAGAA ACCAGAGAAACACACGUUGUGGUACAUrJACCUGGUA GGGAAU ACCAGAGAAACACACGIJUGUGGUACAUIJACCUGGUA GGGAUC ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA GAAGCC ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

CCUCUCG

GGCGGCG

GAGGACG

UCUGGCG

GGGUCCU

GCGCGCU

CUGCUCA

CUCAGCU

GCUGUCU

GGAAGCA

UAAAUCU

GAACACA

UUCUACA

A UUC CCU

GAUCCCU

GGCUUCU

GCU

GCU

GAC

GCC

GCU

GCU

GCU

GUC

GCU

CC

GCC

GCU

GCU

GCC

GAU

GAC

CCUCCCCG

CGGAGCGG

UCUGGCGG

GGGUCGUU

GUGCGCGC

CAGCUGUC

GUCUGCUU

UGCUUCUC

UCUCACAG

CAUAAAUG

UGUGGAAG

CAAGCAAA

GCAAAUAU

GGGUUACG

GGAAAACG

CUGUGAAG

1056 1301 1310 1389 1535 1566 1572 1604 1824 1908 1949 1973 2275 2321 2396 2490 2525 2625 2652 UTUUUJUC AGAA GGGUAA ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA UUACCCU GAU GAAAAAAA GCCGGUAA AGAA UCAUAGAG AGAA AAAUAGCG AGAA UUUCGUAA AGAA AGAGCCGG AGAA GGCUAGAG AGAA CGGUACAA AGAA AUUCUAGA AGAA UUUGGCAC AGAA CUCCUUCC AGAA CUGUGCAA AGAA AGUOGUGO AGAA ACCAAGUG AGAA UUUCAAUA AGAA GUUCCUIJG AGAA UUAGAGUG AGAA .GAUAGGUA AGAA GGAACUUC AGAA

GCUUGC

GGUAAG

GAUUUC

GGGGUU

GGAAAC

GGGUCU

GGAUUU

GC CACA

GUGAUA

GCAUUU

GUUUCA

GCUGAU

GAGGCU

GCGUGC

GUGAGG

GCUCCA

GUCUU1Ju

GGGUCC

ACCAGAGAAACACACGUUTGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJTGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJUGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUIUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGA.AACACACGUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAA.CACACGUUIGUGGUACAUUTACCUGGUA

GCAAGCG

CUUACCG

GAAAUCU

AACCCCA

GUUUCCA

AGACCCG

AAAUCCU

UGUGGCU

UAUCACA

AAAUGCC

UGAAACU

AUCAGCA

AGCCUCA

GCACGCU

CC UCAC U

UGGAGCU

AAAGACU

GGACCCA

GUC

GCU

GCU

GAU

GAC

GCU

GAC

GAC

GAU

GAC

GUC

GUU

GAU

GUU

GUU

GAU

GAC

GAU

UUACCGGC

CUCUAUGA

CGCUAUUU

UUACGAAA

CCGGCUCU

CUCUACCC

UUGUACCG

UCUAGAAU

GUGCCAAA

GGAAGGAG

UUGCACAG

CCACCACU

CACUUGGU

UAUUGAAA

CAAGGAAC

CACUCUAA

UACCUAUC

GAAGUUTCC

2684 2816 2873 2930 2963 3157 3207 3211 3245 3256 3287 3402 3580 3641 3655 3810 3846 3873 3995

CAUAAGGG

CAGCCACA

GCUCAGUC

AGGCUCCC

CAAUCACC

UUCCUGAA

UAGAAACC

CUUGUAGA

UGUAAGAA

CACIJUGAA

IJUCUGGAA

CUCACAUA

CCUCAGGC

CCAGCAUG

UCUGUGCC

UCAGAGAA

AACUUCGG

CUGACAUC

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCUCAC

GGCACG

GAGCU

GGUUAA

GAGC C

GGAGCU

GAAUCC

GUCAGA

GAUCUU

GUAAGA

GGAACU

GGGUUC

GCAAAA

GAUAGA

GUCCAG

GGAGUU

GAAAUA

GAGCUU

ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUU!GUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUIJGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUrGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUrACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUPJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUYACCUGGUA

GUGAGCG

CGUGCCG

AAGCUCU

IJUAACCU

GGCCUCU

AGC U CCG

GGAUUCU

UCUGACG

AAGAUCU

UCUUACA

AG UUCC U

GAACCCC

UUULJGCA

UCUAUCA

CUGGACU

AACUCCU

UAIJUUCA

AAGCUCU

GCACUCU

GCU

GAC

GAU

GCU

GAU

GCU

GAC

GUU

GAU

GUJ

GUC

GAU

GUC

GAU

GCU

GCC

GCU

GAU

GUU

CCCIJUAUG

UGUGGCUG

GACUGAGC

GGGAGCCU

GGUGAUUG

UIJCAGGAA

GGUUIJCUA

UCUACAAG

UUCUUACA

U'UCAAGUG

UTUCCAGAA

UAUGUGAG

GCCUGAGG

CAUGCUGG

GGCACAGA

UUCUCUGA

CCGAAGUU

GAUGUCAG

GGCCUCUC

GAGAGGCC AGAA GAGUGC ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA a a. a. a a. a. a a. a. .a a a.

a a a a a a a a a a a a a a a a. 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

CUGCUGAC

AUGGCAGA

GUGCCCAC

GGGCGGGG

AGUICUGGG

GAGUUGUA

CAAAAAGC

UCACAAAA

GGGGUUGG

CUCAAUCA

AIJUGGGUG

GGCUGCAG

GGGUUUUG.

AGGGUCAG

GUAGAAGG

CGCUGUCC

CUGUGCAA

CUCCUCAG

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

ACAA

AGAA

AGAA

AGAA

AGAA

GACAGC

GGGCCU

GGAAUG

GCACGC

GGGAGC

GGGGGC

GGCUCC

GCUGGC

GGGAAG

GGUCCU

GUGCAG

GGCCCA

GCAGGG

GGGAAG

GAGCUG

GCUCCU

GAAUAA

GCAUUU

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAAcACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGLTJIGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAJACACACG1JUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJTGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJIGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

CGGGGCU

GCUGUCU

AGGCCCA

CAUUCCA

GCGUGCU

GCUCCCC

GCCCCCA

GGAGCCA

GCCAGCU

C UUC CCU

AGGACCA

CUGCACU

UGGGCCA

CCCUGCA

CLJUCCCA

CAGCUCU

AGGAGCA

UUAUUCU

AAAUGCA

GUC

GAU

GUU

GCU

GCU

CC

GAC

GCU

GCU

GCU

GIU

GAU

GCC

ccc

GCU

GAC

GAU

GUU

GUC

UGAUGUCA

GUCAGCAG

UCUGCCAU

GUGGGCAC

CCCCGCCC

CCCAGACU

UACAACUC

GCUUUJUG

UUUUGUGA

C CAA CCC C

UGAUUGAG

CACCCAAU

CUGCAGCC

CAAAACCC

CUGACCCU

CCUUCUAC

GGACAGCG

UUGCACAG

CUGAGGAG

S.

S

*SS

S S SS S S *S

S

555 S S S S S S 55 S *S 55 5 S S *S S 5* 55 5 55 5 5 S S S S S S S S .5 5 5 555 5 5319 5358 5392 5563 5622 5738 5838 5933 6022 6120 6163 6270 6412 6511 6778 6826 7245 7258 UUUcctucc

GGUAUAGA

UGGGUCCC

UGAGUCCC

AGULTUCAA

UAGCAUCA

UAGCAUCA

CCCCAAGA

CACAUAAG

UCCACAAA

GUGGAGAG

AAAUUGCC

AAGACAUG

UUUGAAGG

UCCACCCA

ACIJUCUUG

AACAUAAA

UGGAAGGA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCCCUC

GGGUCU

GUGIJUG

GGAGAA

GUUGAA

GAGCCA

GAGCCA

GCAAUC

GAGGCA

GCUGCC

GUCCCA

GUCACA

GCUAAG

GAGUAA

GUUCCA

GACAAG

GUUGCC

GAACAU

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUtACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUJTGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGTJGGUACAUUACCUGGUA

ACCAGAGAAZ\CACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJ1ACCUGGUA ACCAGAGAAACACACGU1JGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJIGUGGUACAUJ1ACCUGGUA A CCAGAGAAACACACGUIJGUGGUACAU!JACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

GAGGGCU

AGACCCC

CAACACA

UUCUCCA

UUCAACU

UGGCUCU

UGGCUCU

GAUUGCU

UGCCUCU

GGCAGCG

UGGGACA

UGUGACA

CUUAGCU

UUACUCA

UGGAACA

CUUGUCA

GGCAACU

AUGUUCU

GAU

GUC

GUU

GUtJ

GCU

GUU

GUU

GCU

GU1J

GCU

GUC

GCU

GUU

GCU

GUC

GUC

GCU

GUC

GGAGGAAA

UCUAUACC

GGGACCCA

GGGACUCA

UUGAAACU

UGAUGCUA

UGAUGCUA

UCUUGGGG

CUUAtJGUG

ULIUGUGGA

CUCUCCAC

GGCAAUUU

CAUGUCUU

CCUUCAAA

UGGGUGGA

CAAGAAGU

UUUAUGUU

7433 CCCAUACA AGAA GCUAAA ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA UUUAGCU GAU UGUAUGGG 0 7512 7606 7618 7633 U1JRJCAUG AGAA GGAAUU ACCAGAGAAACACACGUUGUGGUACAU1JACCUGGUA GACAUUCA AGAA GAAAUG ACCAGAGAAACACACGUUGUGGUACAUIJACCUGGUA AAUAUAUA AGAA GACAUU ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA AUACAAAG AGAA GAGAAU ACCAGAGAAACACACGUUGUGGUACAUUIACCUGGUA AAUUCCU GUC CAUGAAAA CAUUUCA GCC UGAAUGUC AAUGUCU GCC UAUAUAUU AUUCUCU GCU CUUUGUAU Table IV: Human KDR VEGF Receptor-Hammerhead Ribzm n Substrate Sequence HH-R'ibozyme Sequence Substrate Positior 22.

33 56 64 10 65 75 76 77 15 79 81 85 96 102 20 114 117 118 123 124 130 133 139 141 142 147 148 151

CACAGGGC

UCCACGCP.

AACCCACA

ACUAGGCA

CACUAGGC

AGAAACAC

UCAAGAGA

AUCAAGAG

GAUCAAGA

CAGAUCAA

GGCAGAUC

CCUGGGCA

UGUAUGCU

UCUUUUUG

ALTUGUAAG

UTUAAUUGU

CUtJAAUUG

UTUAGCCUU

AUUAGCCU

AGUUGUAU

AAGAGUUG

AAtUTJGAA

GUAAUUUG

AGUAAUUUJ

CUGCAAGU

CCUGCAAG

UCCCCUGC

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 CUGAUGA2 X GA-7 X GPJ X GAJ

GAP~

GAP

X GAP X GAA X GAA

GAA

GAA

GAA

X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA X GAA K GAA K GAA C GAA C GAA

CGAA

~ACGGCCAG

SAGCCACAG

AGGCGGCC

ACCCACAG

AACCCACA

AGGCAAAC

ACACUAGG

AACACUAG

AAACACUA

AGAAACAC

AGAGAA.C

AUCAAGAG

AGCCUGGG

AUG CUGAG

AUGUCUUU

AGUAUGUC

AAGUAUGU

AUUGUAAG

AALUJGUAA

AGCCUUAA

AUUAGCCU

AGUtJGUAU

AGAGUUGU

AAGAGUUG

AUTUUGAAG

AAUUUGAA

AGUAAUU

CUGGCCGUC

CUGUGGCUC

GGCCGCCUC

CUGUGGGUU

UGUGGGUUU

GUUtJGCCUA

CCUAGUGUU

CUAGUGUUU

UAGUGUTUUC

GUGUUUCUC

GUUIJCUCUU

CUCUUGAUC

CCCAGGCUC

CUCAGCAUA

AAAGACAUA

GACAUACUU

ACAUACUUA

CUtJACAAtUU

UUACAAUTUA

UUTAAGGCUA

AGGCUAAUA

AUACAACUC

ACAACUCUU

CAACUCUUC

CLUCAAALU

UUCAAAUUA

AAAUUtACUU

GCCCUGUG

UGCGUGGA

UGUGGGJUU

UGCCUAGU

GCCUAGUG

GUGUUUCU

UCUCUUTGA

CUCUTUGAU

UCUUGAUC

UtJGAUCUG

GAUCUGCC

UGCCCAGG

AGCAUACA

CAAAAAGA

CIJUACAAU

ACAAUTUAA

CAAUTUAAG

AAGGCUAA

AGGCUAAU

AUACAACU

CAACUCU

UtJCAAALTU

CAAALTUAC

AA.AUUACU

ACUUGCAG

CUUGCAGG

GCAGGGGA

t a.

a a a a a a 170 180 181 190 193 243 245 246 250 258 264 265 276 296 15 305 306 308 323 329 20 333 336 337 338 342 344 348 349 355 356 362 364 368 369

GCCAGUC(

UUGGGCCI

AUUGGGCC

ACUCUGAt

GCCACUCL

UUACAGAP

UCUUACAC

GUCUUACP

GAGUGUCJ

GGAAUUGUJ

ACTUULJUGG

CACUULTUG

UCAUUUCC

AGCACUUG

CCCGGUAG

UCCCGGUA

UUUCCCGG

CCGAGGCC

AAAUGACC

ACAUAAAU

UAGACAUA

AUAGACAU

CAUAGACA

UGAACAUA

CUUGAACA

UAAUCUJG

GUAAUCLU

AGAUCUGU

GAGAUCUG

UAAAUGGA

AAUAAAUG

AAGCAAUA

GAAGCAAU

-CUGAUGA

k CUGAUGA

ICUGAUGA

JCUG AUGA

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

CUGAUGA I

CUGAUGA

CUGAUGA2 CGAA AGUCCCUC C GAA AGCCAGUC GAA AAGCCAGU GAA AUUGGGCC GAA AUUALUUGG GAA AGGCCAUC GAA AGAGGCCA GAA AAGAGGCC GAA ACAGAAGA GAA AGUGUCUU GAA AUUGUGAG GAA AALUGUGA GAA AUCACUUU GAA AGGCUCCA GAA AGCACUTUG GAA AAGCACUU GAA AGAAGCAC GAA AGUCAGUU GAA AGGCCAAG GAA ACCGAGGC GAA AUGACCGA GAA AAUGACCG GAA AAAUGACC GAA ACAUAAAU GAA AGACAUA\ GAA ACAUAGAC GAA AACAUAGA GAA AUCUTUGAA GAA AAUCUUJGA GAA AUCUGUAA GAA AGAUCUGU GAA AUGGAGAU GAA AAUGGAGA

GAGGGACUI

GACUGGCUTI

ACUGGCULTI

GGCCCAAU]

CCAAUAAUC

GAUGGCCUC

UGGCCUCLTL

GGCCUCUTUC

UCUUCUGUP

AAGACACUC

CUCACAAUU

UCACAAUUC

AAAGUGAUC

UGGAGCCUA

CAAGUGCUU

AAGUGCUUC

GUGCUUCUA

AACUGACJUU

CUUGGCCUC

GCCUCGGUC

UCGGUCAUU

CGGUCAUJU

GGUCAUUUA

AUULUAIJGUC

UUAUGUCUA

GUCUAUGUU

UCUAUGUUC

UUCAAGAUU

UC.AAGAUTUA

UUACAGAUC

ACAGAUCUC

AUCUCCAUU

UCtJCCAUUU J GGACUGGC J UGGCCCAA J GGCCCAAU k AUCAGAGU

AGAGUGGC

UUCUGUAA

J CUGUAAGA

UGUAAGAC

AGACACUC

ACAALTUCC

CCAAAAGU

CAAAAGUG

GGAAAUGA

CAAGUGCU

CUACCGGG

UACCGGGA

CCGGGAAA

GGCCUCGG

GGUCALUU

ALTUUAUGU

UAUGUCUA

AUGUCUAU

UGUCUAUG

UAUGUUCA

UGUtJCAAG

CAAGAUJLA

AAGAUTUAC

ACAGAUCU

CAGAUCUC

UCCAUUJUA

CAUUUALU

UAUUGCLU

AUUGCLTUC

370 AGAAGCAA CUGAUGA X GAA AAAUGGAG CUAUt UG UU CUCC-ALTUUA

UUGCUUCU

S

*9eS h S 6S 0O

S

*5S6

S.

S S

J*.

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

ACAGAAG(

ACUAACAC

CACUAACI

UGGUCACL

UUGGUCAC

AUGUACAC

CAGUAAUC

LTUCUCAGTJ

GUUCUCAG

AGACAUGG

GAGACAUG

GGACCCGA

AUGGACCC

UUGAAAUG

AGAUULUGA

GAGAUTUUG

UGAGALUU

CACGUUIGA'

GACACGUU

CACAAAGU

CUUGCACA

UCUUGCAC

UULUCUGGG

CAGGAACA

UCAGGAAC

CCAUCAGG

ACCAUCAG

AAUUCUGU

UCCCAGGA

GUCCCAGG

UGUCCCAG

CUGAUGA

CUGAUGA

SCUGAUGA

J CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CtJGAUGA I CUGAUGA2 CUGAUGA I CUGAUGA CUGAUGA CUGAUGA CUGAUGA Y~ K GAA AUAAAUGG K GAA AGCAAUAA ,K GAA AAGCAAUA CGAA ACAGAAGC C GAA AACAGAAG C GAA ACUCCAUG C GAA ACACGACU GAA AUGUACAC GAA AAUGUACA GAA AUCACCAC GAA AAUCACCA GAA ACAUGGAA GAA AGACAUGG GAA ACCCGAGA GAA AUGGACCC GAA AAUGGACC GAA AAAUGGAC GAA AUUUGAAA GAA AGAUUUGA GAA ACACGUUG GAA AGUGACAC GAA AAGUGACA GAA AUCUUGCA GAA AUCUCUUU GAA AAUCUCUU GAA ACAAAUCU GAA AACAAAUC GAA ACCAUCAG GAA AUUCUGUU GAA AAUUCUGU GAA AAAUTUCUG CCALTLJUAU1f LTUAUJGCL71

UAUJGCUUC

GCUUCUGUt

CUUCUGUU[J

CAUGGAGUC

AGUCGUGU;

GUGUACAUL

UGUACAUU;P

GUGGUGA~LJ

UGGUGAUUC

UUCCAUGUC

CCAUGUCUC

UCUCGGGUC

GGGUCCAUUI

GGUCCAUUU

GUCCAUUUC

UUUTCAAAUC

UCAAAUCUC

CAACGUGUC

GUGUCACUJ

UGUCACUUU

UGCAAGAUA

AAAGAGAUU

AAGAGAUUU

AGAUUITJGUU

GAUUUTGUJC

CUGAUGGUA

AACAGAAUU

ACAGAAUUU

CAGAALUUC

J GCUUCUGU J CUGUUAGU .UGtJUAGUG J AGUGACCA

GUGACCAA

GUGUACAU

CAUUACUG

TACUGAGAA

LCUGAGAAC

ICCAUGUCU

CAUGUCUC

UCGGGUCC

GGGUCCAU

CAUTUUCAA

UCAAAUCU

CAAAUCUC

AAAUCUCA

UCAACGUG

AACGUGUC

ACUUtJGUG

UGUGCAAG

GUGCAAGA

CCCAGAAA

UGUUCCUG

GUUCCUGA

CCUGAUGG

CUGAUGGU

ACAGAAUU

UCCUGGGA

CCUGGGAC

CUGGGACA

S

*S.

5

S

OS S

S

548 GAAUAGUA CUGAUGA X GAA AGCCCLlJC GAGCUUCA GAAGGGCUU UACUAUUC 100

C

C. C

C

549 550 553 555 556 563 570 575 588 590 591 606 607 619 620 626 628 630 631 20 635 639 642 645 648 651 656 658 663 664 665 675 676 682

GGAAUAGU

GGGAAUAG

GCUGGGAA

UAGCUGGG

GUAGCUGG

UGAUCAUG

GCAUAGCU

UGCCAGCA

UCACAGAA

CTUtCACAG

GCUUCACA

UCAUCALU

UUCAUCAU

AGACUGGU

UAGACUGG

ACAUAAUA

GUACAUAA

AUGUACAU

UAUGUACA

CAACUAUG

ACGACAAC

ACAACGAC

CCUACAAC

UACCCUAC

CUAUACCC

AAAUCCUA

AUAAAUCC

ACAUCAUA

CACAUCAU

CCACAUCA

GGACUCAG

CGGACUCA

AUGAGACG

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGA-UGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGA-UGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA:

*GAA AAGCCCUU *GAA AAAGCCCU GA-A AGUAAAGC GA-A AUA-GUAAA GAA AAUAGUAA GA-A AGCUGGGA GA-A AUCAUGUA GA-A AGCUGAUC GAA ACCA-UGCC GA-A AGACCAUG GA-A AA-GA-CCAU GAA AUUUUUIGC GAA A-AUUUUUG GAA A-CUtJUCAU GAA A-ACUUUCA GA-A ACUGGUAA GAA AGA-CUGGU GAA AUAGA-CUG GA-A AAUAGACU GA-A ACA-UAAUA GAA A.UGUACAU GA-A ACUAUGUA GAA A-CAACUAU GA-A ACGACAAC GA-A ACAA-CGAC GA-A A-CCCUACA GAA AUACCCUA- GA-A AUCCUAUA GA-A A-AUCCUAU GA-A AAAUCCUA GAA ACCACAUC GAA A-ACCACAU GA-A A-CUCA-GAA

A-AGGGCUUL

A-GGGCUUUP

GCUTUUACUP

UUUACUAUU

UUACUAUJC

UCCCAGCUA

UACAUGAUC

GA-UCAGCUA

GGCA-UGGUC

CAUGGUCUU

A-UGGUCUUC

GCAAAAALTU

CAAAAAUUA

AUGA-AAGUU

UGAAAGUUA

UUA-CCAGUC

A-CCAGUCUA

C-AGUCUAUJ

AGUCUA-UUA

UA-UUAUGUA

A-UGUACAUA

UACAUAGUU

AUAGUUGUC

GUUGUCGUU

GUCGUUGUA

UGUAGGGUA

UAGGGUAUA

UAUAGGAUU

A-UAGGAULU

UAGGAUUUA

GA-UGUGGUU

A-UGUGGUILJC

LUUCUGAGUC

T ACUAUUCC

CUA-UUCCC

*UUCCCAGC

CCCAGCUA

*CCAGCUAC

*CAUGAUCA

AG CUAUG C

UGCUGGCA

UIJCUGUGA

CUGUGAAG

UGUGAAGC

AAUGAUGA

AUGA-UGAA

A-CCAGUCU

CCAGUCUA

UAUUAUGU

UTUA-UGUAC

A-UGUACAU

UGUA-CAUA

CA-UA-GLTUG

GUUGUCGU

GUCGUUGU

GUUGUAGG

GUAGGGUA

GGGUAUAG

UAGGAUUUTE

GGAUUUAU

UA-UGAUGU

AUGAUGUG

UGA-UGUGG

CUGA-GUCC

UGAGUCCG

CGUCUCAU

686 688 696 702 704 708 720 723 725 726 730 733 750 762 767 768 779 784 785 787 788 796 802 810 813 825 836 857 858 859 860 869 870

UUCCAUGA

AAUUCCAU

GAUAGUUC

CCAACAGA

CUCCAACA

UUJUucUcc

UUUAAGAC

CAAUtJUAA

UACAAULTLJ

GUACAAUU

UGCUGUAC

UCUUGCUG

CCCACAUU

UUGAAGUC

CCCAGUTUG

UCCCAGUT

AAGAAGGG

CUtJCGAAG

GCUUCGAA

AUGCUUCG

GAUGCUUC

CUUAUGCU

AAGUUUCU

CGGUTUUAC

UCUCGGUU

UGGGULUU

CUGAUGA X GAA ACGGACUC CUGAUGA X GAA AGACGGAC CUGAUGA X GAA AUUCCAUG CUGAUGA X GAA AGUUCAAU CUGAUGA X GAA AUAGUUCA CUGAUGA X GAA ACAGAUAG CUGAUGA X GAA AGCUUUUC CUGAUGA X GAA ACAAGCUU CUGAUGA X GAA AGACAAGC CUGAUGA X GAA AAGACAAG CUGAUGA X GAA AUUUAAGA CUGAUGA X GAA ACAAUUUA CUGAUGA X GAA AGUUCAGU CUGAUGA X GAA AUCCCCAC CUGAUGA X GAA AGUCAAUC CUGAUGA X GAA AAGUCAAU CUGAUGA X GAA AUUCCCAG CUGAUGA X GAA AGGGUALU CUGAUGA X GAA AAGGGUAU CUGAUGA X GAA AGAAGGGU CUGAUGA X GAA AAGAAGGG CUGAUGA X GAA AUG CUUCG CUGAUGA X GAA AUG CUGAU CUGAUGA X GAA AGUTUUCUU CUGAUGA X GAA ACAAGUUU CUGAUGA X GAA AGGUCUCG GAGUCCGUC UCAUGGAA GUCCGUCUC AUGGAAUU CAUGGAAUU GAACUAUC AUUGAACUA UCUGUUGG UGAACUAUC UGUUGGAG CUAUCUGUU GGAGAAAA GAAAAGCUU GUCUUAAA AAGCUIJGUC UUAAAUUG GCUUGUCUU AAAUUGUA CUUGUCUUA AAUUGUAC UCUUAAAUU GUACAGCA UAAAUUGUA CAGCAAGA ACUGAACUA AAUGUGGG GUGGGGAUU GACUUCAA GAUUGACUU CAACUGGG AUUGACUUC AACUGGGA CUGGGAAUA CCCUTUCLU AAUACCCUU CUUCGAAG AUACCCUUC UUCGAAGC ACCCUUCUFU CGAAGCAU CCCCUC GAAGCAUC CGAAGCAUC AGCAUAAG AUCAGCAUA AGAAACUU AAGAAACUU GUAAACCG AAACUUGUA AACCGAGA CGAGACCUA AAAACCCA AACCCAGUC UGGGAGUG GAAGAAAUU UUUGAGCA AAGAAAUUU UUGAGCAC AGAAAUTUUU UGAGCACC GAAAUUUUU GAGCACCU GAGCACCUU AACUAUAG AGCACCUUA ACUAUAGA CACUCCCA CUGAUGA X GAA ACUGGGUU UGCUCAAA CUGAUGA X GAA AUUUCLTEJC GUGCUCAA CUGAUGA X GAA AAUUtJCUU GGUGCUCA CUGAUGA X GAA AAAUUUCU AGGUGCUC CUGAUGA X GAA AAAAUUUC CUAUAGUU CUGAUGA X GAA AGGUGCUC UCUAUAGU CUGAUGA X GAA AAGGUGCU 102

A

A.

A

A

A A

A

874 876 885 905 908 923 956 957 960 966 979 980 981 984 988 989 990 1007 1009 1038 1044 1055 1059 1063 1064 1080 1088 1090 1101 1107 1112 1117

ACCAUCU

ACACCAU(

CUCCGGGI

AGGUGUAC

CACAGGUC

GCCCACUC

CCCUGAC.

ACCCUGAC

UGGACCCL

UUUTJCAUC

AGCAACA.A

AAGCAACA

AAAGCAAC

CCAAAAGC

ACUUCCAA

CACUUCCA

CCACUUCC

CCACCAGA

UtJCCACCA

GGGAUUCU

UUCGCAGG

AACCAAGG

GGGUAACC

GGGUGGGU

GGGGUGGG

UACCAUUU

CAUUUUUA

UCCAUUUU

UCAAGGGG

UEJGGACUC

UGUGAUUG

AALTUGUGU

k. CUGAUGA 2 CUAG J CtJGAUGA

:CUGAUGA

.7 CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

TCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA CUGAUGA 2

CUGAUGA

CUGAUGA

CUGAUGA N~ CUGAUGA Y CUGAUGA X CUGAUGA X X GAA AGUUAAGG K GAA AUAGUUAA K GAA ACACCAUC K GAA AUCCUUGG C GAA ACAAUCCU C GAA AUGCUGCA C GAA AUGUGCUG IGAA AAUGUGCU .GAA ACAAAUGU GAA ACCCUGAC GAA AGGUUUUU GAA AAGGUtUU GAA AAAGGUUU GAA ACAAAAGG GAA AGCAACAAi GAA AAGCAACA GAA AAAGCAAC GAA AUUCCAUG GAA AGAUUCCA GAA ACACGCUC GAA AUtJCUGAC GAA ACUTUCGCA GAA AGGUACUU GAA ACCAAGGU GAA AACCAAGG GAA AUUUCUGG GAA ACCAUULU GAA AUACCATU GAA AUUCCAUU GAA AGGGGUAU GAA ACUCAAGG GAA AUUGGACU

CCUUAACU

UUAACUAU

GAUGGUGU

CCAAGGAU

AGGAUUGU

UGCAGCAU

CAGCACAU

AGCACAUUI

ACAUUUGU(

GUCAGGGU(

AAAAAC CUE

AAAACCUUL

AAACCUUU

CCUUUUGUL

UUGUUGCUL

UGUUGCUUU

GUUGCULUU

CAUGGAAUC

UGGAAUCUC

GAGCGUGUC

GUCAGAAUC

UGCGAAGUA

AAGUACCUU

ACCUTUGGLU

CCUtJGGUUA

CCAGAAAUA

AAAAUGGUA

AAUGGUAUA

AAUGGAAUA

AUACCCCIU

CCUUGAGUC

AGUCCAAUC

A UAGAUGGU A GAUGGUGU A ACCCGGAG U3 GUACACCU A. CACCUGUG

CAGUGGGC

J UGUCAGGG J GUCAGGGU AGGGtJCCA 7 CAUGAAAA J tJUGUUGCU J UGUUGCULJ JGUUGCUUtJ

TGCUUUUGG

rUUEGGAAGU rUGGAAGUG

GGAAGUGG

UCUGGUGG

UGGUGGAA

AGAAUCCC

CCUGCGAA

CCUTUGGUU

GGUUACCC

ACCCACCC

CCCACCCC

AAAUGGUA

UAAAAAUG

AAAAUGGA

CCCCUUGA

GAGUCCAA

CAAUCACA

ACACAALU

1125 CCCGCUUU CUGAUGA X GAA AUUGUGUG CACACAAUU AAAGCGGG 103 1126 1140 1149 1150 1180 1181 1188 1191 1194 1195 1201 1206 1207 1208 1233 1235 1237 1242 1247 1251 1263 1274 1276 1278 1281 1283 1285 1294 1295 1298 1304 1315 1330 CCCCGCUt.J

AUCGUCAC

ACUUCCAUJ

CACUUCCA

GACAGUGU

UGACAGtJG

GUAAGGAU

UUGGUAAG

GGAUtJGGU

GGGAUTUGG

UGAAAUGG

UCCULUGA

CUCCUUUG

UcUccUrJ

ACCAGAGA

CAACCAGA

CACAACCA

ACAUACAC

GUGGGACA

UGGGGUGG

UTUCUCACC

AGAUTUAGA

AGAGAUUA

GGAGAGAU

ACAGGAGA

CCACAGGA

AUCCACAG

CUGGUAGG

ACUGGUAG

CGUACUGG

UGGUGCCG

CAGCGUUU

AUAGACCG

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

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAA AAUTJGUGU GAA ACAUGCCC GAA AUCGUCAG GAA AAUCGUCA GAA AUTUUCCUG GAA AAUUUITCCU GAA ACAGUGUA GAA AUGACAGU GAA AGGAUGAC GAA AAGGAUGA GAA AUTJGGUAA GAA AUGGGAIJJ GAA AAUGGGAU GAA AAAUGGGA GAA ACCACAUG GAA AGACCACA GAA AGAGACCA GAA ACCAGAGA GAA ACACAACC GAA ACAUACAC GAA AUCUGGGG GAA AUUUCUCA GAA AGAUTUUCU GAA AGAGAUUUJT GAA AUUAGAGA GAA AGAUUJAGA GAA AGAGALUJA GAA AUCCACAG GAA AAUCCACA GAA AGGAAUCC GAA ACUGGUAG GAA AGUGGUGC GAA ACAUGUCA

C

ACACAAULJA

GGGCAUGUA

CUGACGAUU

UGACGAUtJA

CAGGAAAUU

AGGAAAUUA

UACACUGUC

ACUGtJCAUC

GUCAUCCU

UCAUCCUtJA

UUACCAAUC

AAUCCCALU

AUCCCAUU

UCCCAUUUC

CAUGUGGUC

UGUGGUCUC

UGGUCUCUC

UCUCUGGUU

GGUUGUGUA

GUGUAUGUC

CCCCAGAUU

UGAGAAAUC

AGAAAUCUC

AAAUCUCUA

UCUCUAAUC

UCUAAUCUC

UAAUCUCUC

CUGUGGAUU

UGUGGAUUC

GGAUUCCUA

CUACCAGUA

GCACCACUC

UGACAUGUA

'AAGCGGGG

CUGACGAU

AUGGAAGU

UGGAAGUG

ACACUGUC

CACUGUCA

AUCCUJAC

CUUACCAA

ACCAAUCC

CCAAUCCC

CCAUUTUCA

UCAAAGGA

CAAAGGAG

AAAGGAGA

UCUCUGGU

UCUGGUTUG

UGGUUGUG

GUGUAUGU

UGUCCCAC

CCACCCCA

GGUGAGAA

UCUAAUCU

UAAUCUCU

AUCUCUCC

UCUCCUGU

UCCUcUGG

CUGUGGAU

CCUACCAG

CUACCAGU

CCAGUACG

CGGCACCA

AAACGCUG

CGGUCUAU

104 1335 AUGGCAUA CUGAUGA X GAA ACCGUACA UGUACGGUC UAUGCCAU S C

S

S

S

.55.

S

S

555555 1337 1344 1345 1348 1357 1362 1370 1372 1379 1416 1418 1433 1438 15 1466 1467 1480 1485 1491 20 1492 1495 1501 1505 1506 1510 1512 1515 1536 1540 1545 1548 1549 1551 GAAUGGC2

GGGGGAGC

CGGGGGAC

AUGCGGGC

GUGGAUGt

UACCAGUC

ACUGCCA;

CAACUGC C

CUTJCCUCC

GUCACUG.A

UUGUCACUJ

CACAAGGG

LUUCUIJCAC

CUCCCUGG

CCUCCCUG

UEJCAAUUU

UUAACUUC

UUUUUTAUU

AUUUUJAU

ULJGAUUUU

AGCAAAUU

UtJAGAGCA

AUUAGAGC

LUCAALUA

CCUTUCAAU

UUCCUUC

AGGGUACU

AACAAGGG

UGGAUAAC

GCUTUGGAU

CGCUUGGA

GCCGCUUG

k. CUGAUGA 37 CUGAUGA

CUGAUGA

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

CUGAUGAI

CUGAUGA I CUGAUGA CUGAUGA 3 C GAA AGACCGUA C GAA AUGGCAUA I GAA AAUGGCAU I GAA AGGAAUGG CGAA AUGCGGGG 'GAA AUGUGAUG GAA ACCAGUGG GAA AUACCAGU GAA ACUGCCAA GAA ACAGCUTUG GAA AGACAGCU GAA AUGGGUUU GAA AGGGUAUG GAA AGUCCUCC GAA AAGUCCUC GAA AUUTUCCUC GAA AUUUUAUU GAA ACUUCAAU GAA AACUUCAA GAA AUUAACU GAA AUUUUUAU GAA AUUGAUUU GAA AAUTUGAUU GAA AGCAI4AUU GAA AGAGCAAA GAA AUUIAGAGC GAA ACAGUUUU GAA ACUACAG GAA AGGGUACU GAA ACAAGGGU GAA AACAAGGG GAA AUAACAAG

UACGGUCUI

UAUGCCAUt

AUGCCAUUC

CCAUUCCUC

CCCCGCAUC

CAUCACAUC

CCACUGGUA

ACUGGUAUU

UUGGCAGtUt

CAAGCUGUC

AGCUGUCUC

AAACCCAUA

CAUACCCUU

GGAGGACUU

GAGGACUUC

GAGGAAAUA

AAUAAAAUU

AULJGAAGU

UUGAAGUUA

AAGUUAAUA

AUAAAAAUC

AAAUCAAUU

AAUCAAUUU

AALUUJGCUC

UJUUGCUCUA

GCUCUAAUU

AAAACUGUA

CUGUAAGUA

AGUACCCUU

ACCCUUGUU

CCCUUGtJUA

CUUGUUAUC

kUGCCAUUC iCCtTCCCCC

CUCCCCCG

CCCCGCAU

ACAUCCAC

CACUGGUA

UUGGCAGU

GGCAGUTUG

GGAGGAAG

UCAGUGAC

AGUGACAA

CCCUUGUG

GUGAAGAA

CCAGGGAG

CAGGGAGG

AAAUUGAA

GAAGUTUAA

AAUAAAAA

AUAAAAAU

AAAAUCAA

AAULTLJGCU

UGCUCUAA

GCUCUAAU

UAAUUGAA

ALTUGAAGG

GAAGGAAA

AGUACCCU

CCCUUGUU

GUUAUCCA

AUCCAAGC

UCCAAGCG

CAAGCGGC

105 1568 ACAAAGCU CUGAUGA X GAA ACACAUUU a 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

UUJUGUAC;

AUUEJGUAC

CACAUUUC

ACUULGUL

CCUCUccc

UGGAAGGP

CGUGGAAG

UCACGUGG

GUCACGUG

AAUUUCAG

UGCAAAGU

LTUGCAAAG

AGGUTUGCA

CAGGUUGC

ACCACAAA

GCACCACA

UGCACCAC

CAAACGUA

CUCAAACG

GGUUCUCA

AGGUUCUC

UACCAUGU

CAAGCUUG

UGUGGGCC

GAUUGGCA

CCCACAUG

GUGUGGGC

UtJCUUGCA

GUTUCUULGC

GAGUAUCC

CCAAAGAG

UUUCCAAA

CUGAUGA

CUGAUGA

CUGAUGA

F 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

CUGAUGA

CUGAUGA

*GAA AGCUGACA .GAA AAGCUGAC GAA ACAAAGCU GAA ACCGCUUC GAA ACUUUGLU GAA AUCACCCU GAA AGAUCACC GAA AGGAGAUC GAA AAGGAGAU GAA ACCCCUGG GAA AUTUUCAGG GAA AAUJUCAG GAA AGUAAUUJ GAA AAGUAAUU 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 AGUUCUUG GAA AUCCAAGU GAA AGUAUCCA AAAUGUGUC AGCUUTUGU UGUCAGCUU UGUACAAA GUCAGCUUU GUACAAAU AGCUUUGUA CAAAUGUG GAAGCGGUC AACAAAGU AACAAAGUC GGGAGAGG AGGGUGAUC UCCUUCCA GGUGAUCUC CUUCCACG GAUCUCCUU CCACGUGA AUCUCCUTUC CACGUGAC CCAGGGGUC CUGAAAUtJ CCUGAAAUU ACUtJUGCA CUGAAAUUA CUUUGCAA AAAUUACUU UGCAACCU AAUUACUUJ GCAACCUG GAGCGUGUC UUUGUGGU GCGUGUCUU UGUGGUGC CGUGUCUUtJ GUGGUGCA AGACAGAUC UACGUUUEG ACAGAUCUA CGUTUUGAG AUCUACGUU UGAGAACC UCUACGUUU GAGAACCU GAGAACCUC ACAUGGUA CACAUGGUA CAAGCUUG UACAAGCUtJ GGCCCACA CACAGCCUC UGCCAAUC CUGCCAAUC CAUGUGGG GGGAGAGUU GCCCACAC ACACCUGUU UGCAAGAA CACCUGUUtJ GCAAGAAC CAAGAACUU GGAUACUC ACUIJGGAUA CUCUUUGG UGGAUACUC UUTUGGAAA 106 1821 AALTLJUCCA CUGAUGA X GAA AGAGUAUC GAUACUCUU UGGAAALU a 1822 1829 1844 1845 1847 1849 1852 1866 1867 1868 1872 1881 1882 1892 1895 1913 1917 1923 1927 1954 1962 1971' 1977 1980 2001 2020 2032 2034 2046 2052 2054 2066

CAAUUUCC

UGGCAUtJC

UAUUAGAC

CUAUTUAGA

UGCUAUUA

UGUGCUAU

AUUUGUGC

AUGAUCAA

CAUGAUCA

CCAUGAUC

AGCUCCAU

GCAUtJCUU

UGCAULTCU

CCUGCAAG

GGUCCUGC

GGCAGACA

GCAAGGCA

UCUTUGAGC

CCUGUCUU

GACCACGC

AGCUGCCU

AGGACUGU

CGCUCUAG

ACACGCUC

UUUCCUGU

UGUCGUCU

UUCCCCAA

curuucccc

GAGACUTUC

GUGCAUGA

CCGUGCAU

GAL17CCCA

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 I CUGAUGA GAA AAGAGUAU ,GAA AUUUTCCAA *GAA ACAUGGUG GAA AACAUGGU *GAA AGAACAUG GAA AGAGAACA GAA AUUAGAGA GAA AUGUCAUU GAA AAUGUCAU GAA AAAUGUCA GAA AUCAAAAU GAA AGCUCCAU GAA AAGCUCCA GAA AUG CAUTUC GAA AGGAUGCA GAA AGUCUCCU GAA ACAUAGUC GAA AGGCAGAC GAA AGCAAGGC GAA AUGUCLTJU GAA ACCACGCA GAA AGCUGCCU GAA ACUGUGAG GAA AGGACUGU GAA AUCGUGGG GAA AUUCUCCA GAA ACUUGUCG GAA AUACUUGU GAA AUGCUUUC GAA ACUUCGAU GAA AGACUUCG GAA AUG CCGUG

AUACUCUUI.

UUGGAAAat

CACCAUGUJ

ACCAUGUUC

CAUGUUCUC

UGUUCUCUA

UCUCUAAUA

AAUGACAUU

AUGACAUUUJ

UGACAUTUUU

AUUUUGAUC

AUGGAGCUU

UGGAGCUUA

GAAUGCAUC

UGCAUCCUU

AGGAGACUA

GACUAUGUC

GUCUGCCUU

GCCUUGCUC

AAAGACAUU

UGCGUGGUC

AGGCAGCUC

CUCACAGUC

ACAGUCCUA

CCCACGAUC

UGGAGAAUC

CGACAAGUA

ACAAGUALU

GAAAGCAUC

AUCGAAGUC

CGAAGUCUC

CACGGCAUC

JGGAAAUUG

JGAAUGCCA

JCUCUAAUA

UCUAAUAG

UAAUAGCA

AUAGCACA

GCACAAAU

LJUGAUCAU

UGAUCAUG

GAUCAUGG

AUGGAGCU

.AAGAAUGC

AGAAUGCA

CUUGCAGG

GCAGGACC

UGUCUGCC

UGCCUUGC

GCUCAAGA

AAGACAGG

GCGUGGUC

AGGCAGCtJ

ACAGUCCU

CUAGAGCG

GAGCGUGU

ACAGGAAA

AGACGACA

UUGGGGAA

GGGGAAAG

GAAGUCUC

UCAUGCAC

AUGCACGG

UGGGAAUC

107

C

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

2293 2295

UGGAGGGC

GAUCtJGUG

AACCACAJ

UAUCUUU.A

UTUAUCUU

ALUAUCUU

GGUCUCAU

UCUEJCUAC

GAGUCUUC

CAAUGCCU

UTUCAAUAC

UCCUtJCAA

CAUCCUJC

CGGAUAGU

UCUGCGGA

ACUCUGCG

CAGGUGUA

GGCAGGUG

CAGCCAAG

ACAGCCAA

GCACAGCC

UUAUGA AA

AUUAUGAA

UAUUAUGA

CUAUUIAUG

UCUALUAU

CCUUCUAU

GCACCUUC

UGAULJUCC

AGAAUAAU

ACUAGAAU

UACUAGAA

CCUACUAG

CUGAUGA

ICUGAUGA

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:

CUGAUGA:

GAA AUEJCCCAG GAA AGGGGGAU GAA AUCUGUGG GAA ACCACAUG GAA AACCACAU GAA AAACCACA GAA AUCUUUAA GAA AGGGUCUC GAA ACAAGGGU GAA AGUCUUCU GAA AUGCCUGA GAA ACAAUGCC GAA AUACAAUG GAA AGGUTUCCG GAA AGUGAGGU GAA AUAGUGAG GAA AGGCCUUC GAA AGAGGCCU GAA ACACUGCA GAA AACACUGC GAA AGAACACU GAA AUGCCUCC GAA AAUGCCUC GAA AAAUGCCJ GAA AAAAUGCC GAA AAAAAUGC GAA AUGAAAAA- GAA AUUAUGAA GAA AGUUCGUC GAA AUTUUCCAA GAA AUGAUUC GAA AAUGAlUU GAA AUAAUGAU

CUGGGAAUC

AUCCCCCUC

CCACAGAUC

CAUGUGGUU

AUGUGGUUU

UGUGGUTJEUA

UUAAAGAUA

GAGACCCU

ACCCUUGUA

AGAAGACUC

UCAGGCAUUJ

GGCATUtGUA

CAUUGUAUU

CGGAACCUC

ACCUCACUA

CUCACUAUC

GAAGGCCUC

AGGCCUCUA

UGCAGUGUU

GCAGUGUUC

AGUGUUCUU

GGAGGCAUU

GAGGCAUtJU

AGGCAUUUUJ

GGC-AUUUUU

GCAUUUUUC

UUUUtJCAUA

LUJCAUAAUA

GACGAACUU

UUGGAAAUC

GAAAUCALU

AAAUCAUUJA

AUCALUJAUU

CCCCUCCA

CACAGAUC

AUGUGGUU

UAAAGAUA

AAAGAUAA

AAGAUAAU

AUGAGACC

GUAGAAGA

GAAGACUC

AGGCAUTUG

GUAUTUGAA

LTUGAAGGA

GAAGGAUG

ACUAUCCG

UCCGCAGA

CGCAGAGU

UACACCUG

CACCUGCC

CUTUGGCUG

UJUGGCUGU

GGCUGUGC

UTUUCAUAA

UTUCAUAAU

UCAUAAUA

CAUAAUAG

AUAAUAGA

AUAGAAGG

GAAGGUGC

GGAAAUCA

AUTUALUCU

AUUCUAGU

UUCUAGUA

CUAGUAGG

108 2296 GCCUACUA CUGAUGA X GAA AAUAAUGA UCAUUAUUJC UAGUAGGC 2298 2301 2316 2324 2325 2327 2328 2334 2337 2338 2340 2343 2346 2349 2352 2361 2362 2396 2399 2402 2406 2409 2416 2427 2432 2443 2458 2459 2480 2481 2502

GUGCCUA(

GUCGUGCC

AACAUGGC

GCCAGAAC

AGCCAGA7

GUAGCCAC

AGUAGCCA

ACAAGAAC

AUGACAAG-

GAUGACAA

AUGAUGAC

AGGAUGAUJ

CCUAGGAU

GUCCCUAG

ACGGUCCC

GCCCGCUU

GGCCCGCU

UGGACAAG

CGAUGGAC

UGACGAUG

UCCAUGAC

GGAUCCAU

LUCAUCUG

UCCAAUGG

GUUCAUCC

UCGUTUCAC

GGCAUCAU

UGGCAUCA

CUCUGGGG

UCUCUGGG

GGCUUACC

: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 CUGAUGA

CUGAUGA?

CUGAUGA)

CUGAUGA J CUGAUGA Y C GAA AGAAUAAU C GAA ACUAGAAU IGAA AUCACCGU rL GAA ACAUGGCA GAA AACAUGGC 'GAA AGAACAUG 'GAA AAGAACAU :GAA 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

AUUAUUCUA

AUUCUAGUA

ACGGUGAUJ

UGCCAUGUU

GCCAUGUTUC

CAUGUUCJUU

AUGUEJCUUC

UUCUGGCUA

UGGCUACUU

GGCUACUUTC

CUACUTUCUU

CUUCUEJGUC

CLJUGUCAUC

GUCAUCAUC

AUCAUCCUA

GGGACCGUU

GGACCGUtJA

GACAGGCUA

AGGCUACUU

CUACUUGUC

UUGUCCAUC

UCCAUCGUC.

UCAUGGAUC

GAUGAACUC

ACUCCCAUU

AUGAACAUU

GACUGCCLU

ACUGCCLtJA1

AUGGGAAUU

UGGGAAUJUC

CUGAACCUA

GUAGGCAC

GGCACGAC

GCCAUGUU

CUUCUGGC

UUCUGGCU

CUGGCUAC

UGGCUACU

CLUCUGU

CUUGUCAU

UUGUCAUC

GUCAUCAU

AUCAUCCU

AUCCUAGG

CUAGGGAC

GGGACCGU

AAGCGGGC

AGCGGGCC

CUUGUCCA

GUCCAUCG

CAUCGUCA

GUCAUGGA

A1UGGAUCC

CAGAUGAA

CCAUTUGGA

GGAUGAAC

GUGAACGA

kUGAUGCC

JGAUGCCA

CCCAGAG

:CCAGAGA

;GUAAGCC

2506 AAGAGGCU CUGAUGA X GAA ACCUAGGU ACUGAACUCI ACCUAGGUA AGCCUCUU 109 2512 ACGGCCAA CUGAUGA X GAA 0 0 0 0 a a a 0* a 000000 0 000000 2514 2528 2529 2541 2555 2556 2562 2578 2589 2595 2603 2632 2638 2640 2645 2652 2658 2661 20 2664 2665 2668 2670 2674 2680 2682 2691 2697 2698 2700 2710 2730 2739

CCACGGCC

CUUTGGCCA

UCtTUGGCC

UCUGCUUC

CAAUUCCA

UCAAUTUCC

GUCUUGUC

UGUCCUGC

UJUGACUGC

AACAUUUU

cuuUC

GAGAGCUC

AGACAUGA

UCAGACAU

UGAGUUtCA

AGGAUCUU

UGAAUGAG

AUAUGAAU

CCAAUAUG.

ACCAAUAU

GUGACCAA

UGGUGACC

GAGAUGGU

CACAUUGA

ACCACAUU

AGAAGGUU

GCACCUAG

GGCACCUA

CAGGCACC

UGGCUTJGG

AUCACCAU

AAUUCCAC

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

AGGCUUAC

AGAGGCUU

AGGCACCA

AAGGCACC

AUCUCUUG

AGGCAUCU

AAGGCAUC

AUTUCCAAA

AGUUGCUG

ACUGUCCU

ACUGCUAC

ACAUUUUG

AUGCUCAC

AGCUCGAU

AGAG.CUCG

ACAUGAGA'

AGUTUCAGA

AUCUTUGAG

AGGAUCLU

AUGAGGAU

AAUGAGGA

AUGAAUGA

AUAUGAAU

ACCAAUAU

AUGGUGAC

AGAUGGUG

ACCACALU

AGGUTUGAC

AAGGUUGA

AGAAGG2JU

ACAGGCAC

AGUGGCCC

AUCACCAU

GUAAGCCUC

AAGCCUCUU

UGGUGCCUU

GGUGCCUUU

CAAGAGAUU

AGAUGCCUU

GAUGCCUUU

UUUGGAAUU

CAGCAACUU

AGGACAGUA

GUAGCAGUC

CAAAAUGUU

GUGAGCAUC

AUCGAGCUC

CGAGCUCUC

UCUCAUGUC

UCUGAACUC

CUCAAGAUC

AAGAUCCUC

AUCCUCAUU

UCCUCAUUC

UCAUTUCAUA

AUUCAUAUU

AUALTJGGUC

GUCACCAUC

CACCAUCUC

AAUGUGGUC

GUCAACCLU

UCAACCUTUC

AACCUUCUA

GUGCCUGUA

GGGCCACUC

AUGGUGAJU

UUGGCCGU

GGCCGUGG

UGGCCAAG

GGCCAAGA

GAAGCAGA

UGGAAUUG

GGAAUUGA

GACAAGAC

GCAGGACA

GCAGUCAA

AAAAUGUU

GAAAGAAG

GAGCUCUC

UCAUGUCU

AUGUCUGA

UGAACUCA

AAGAUCCU

CUCAUULCA

AUUICAUAU

CAUAUUGG

AUAUUGGU

UUGGUCAC

GGUCACCA

ACCAUCUC

UCAAUGUG

AAUGUGGU

AACCUUCU

CUAGGUGC

UAGGUGCC

GGUGCCUG

CCA:AGCCA

AUGGUGAU

GUGGAAUU

r 110 a. a a a a 2747 2748 2756 2757 2768 2773 2774 2798 2799 2802 2807 2828 2829 2833 2846 2850 2859 2869 2882 20 2892 2899 2909 2918 2924 2925 2939 2943 2952 2968 2977 2981 2983 2990

AUUUGCAC

AAUtJUGC.A

GGUUUCCA

AGGUUUCC

GGUAAGUG

CCUCAGGU

UCCUCAGG

AGGGGACA

UAGGGGAC

UUGUAGGG

UGGUCUUG

CUUJGACGG

CCUTUGACG

uuucCCUtJ

CUCCAACG

AUUGCUCC

UCCACAGG

CCGUUUCA

UGCUGUCC

CUACUGGU

GCUCUGGC

AGCUGGCU

CAAAUCCA

CCUCCACA

UCCUCCAC

CACUGAGG

ACAUCACU

UCUTUCUUC

AUCUUCAG

CUUAUACA

AGUCCUUJA

GAAGUCCU

AGGUCAGG

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 AUUCCACA *GAA AAUTUCCAC GAA AUIJUGCAG GAA AAUTUUGCA GAA ACAGGUU!J GAA AGUGGACA GAA AAGUGGAC GAA AUUCALUUJ GAA AAUTUCAUU GAA ACAAAUTUC GAA AGGGGACA GAA AUCGUGCC GAA AAUCGUGC GAA ACGGAAUC GAA AGUCUUUC GAA ACGUAGUC GAA AUUGCUCC GAA AUCCACAG GAA AGCGCCGU GAA AUGCUGUC GAA ACUGGUGA GAA AGCUCUGG GAA AGCUGGCU GAA AUCCAGAG GAA AAUCCAGA GAA ACUUCUCC GAA AGGGACUU GAA ACAUCACU GAA AGCUTUCCU GAA AUCUTJCAG GAA ACAGAUCU GAA AUACAGAU GAA AGUCCUUA

UGUGGAAUU

GUGGAAUUC

CUGCAAAUU

UGCAAAUUU

AAACCUGUC

UGUCCACUU

GUCCACUUA

AAAUGAAUU

AAUGAAUUU

GAAUUUGUC

UGUCCCCUA

GGCACGAUU

GCACGAUUC

GAUUCCGUC

GAAAGACUA

GACUACGUU

GGAGCAAUC

CUGUGGAUC

ACGGCGCUTJ

GACAGCAUC

UJCACCAGUA

CCAGAGCUC

AGCCAGCUC

CUCUGGAUU

UCUGGAUUU

GGAGAAGUC

AAGUCCCUC

AGUGAUGUA

AGGAAGCUC

CUGAAGAUC

AGAUCUGUA

AUCUGUAUA

UAAGGACUU

CUGCAAAU

UGCAAALU

UGGACC

GGAAACCU

CACUUACC

ACCUGAGG

CCUGAGGA

UGUCCCCU

GUCCCCUA

CCCUACAA

CAAGACCA

CCGUCAAG

CGUCAAGG

AAGGGAAA

CGUTUGGAG

GGAGCAAU

CCUGUGGA

UGAAACGG

GGACAGCA

ACCAGUAG

GCCAGAGC

AGCCAGCU

UGGAUUUG

UGUGGAGG

GUGGAGGA

CCUCAGUG

AGUGAUGU

GAAGAAGA

CUGAAGAU

UGUAUAAG

UAAGbGACU

AGGACIJUC

CCUGACCU

aill a.

a a 2991 2999 3007 3009 3012 3016 3017 3023 3024 10 3034 3047 3048 3050 3056 3067 3069 3094 3096 3099 20 3101 '3102 3104 3120 3121 3126 3134 3135 3140 3151 3153 3154 3155

AAGGUCAG

GAUGCUCC

ACAGAUGA

UAACAGAU

CUGUAACA

GAAGCUGU

GGAAGCUG

CCACLTUGG

GCCACUUG

CAUGCCCU

AUGCCAAG

GAUGCCAA

GCGAUGCC

ACtUUUCGC

CCUGUGGA

UCCCUGUG

UAAGAGGA

GAUAAGAG

UCCGAUAA

UCUCCGAU

UUCUCCGA

UCuTUCUcC

CAGAUUUU

ACAGAUUU

AAGUCACA

CCAAGCCA

GCCAAGCC

CCCGGGCC

UUUIAUAAA

UCULUAUA

AUCUUTUAU

GAUCUUUA

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

AAGUCCU

AGGUCAGG

AUGCUCCA

AGAUGCUC

AUGAGAUG

ACAGAUGA

AACAGAUG

AGCUGUAA

AAGCUGUA

AGCCACUU

ACUCCAUG

AACUCCAU

AGAACUCC

AUGCCAAG

ACACUUUC

AUACACUU

ALTUIJCGUG

AUAUUUCG

AGGAUAUU

AGAGGAUA

AAGAGGAU

AUAAGAGG

ACCACGLU

AACCACGU

AUUUUAAC

AGUCACAG

AAGUCACA

AGCCAAAG

AUCCCGGG

AUAUCCCG

AAUAUCCC

AAAUAUCC

AAGGACUUC

CCUGACCUU

UGGAGCAUC

GAGCAUCUC

CAUCUCAUC

UCAUCUGUU

CAUCUGtJUA

UUACAGCUU

UACAGCUUC

AAGUGGCUA

CAUGGAGUU

AUGGAGUUC

GGAGUUCUU

CULJGGCAUC

GAAAGUGUA

AAGUGUAUC

CACGAAAUA

CGAAAUAUC

AAUAUCCUC

UAUCCUCUU

AUCCUCUUJA

CCUCUUAUC

AACGUGGUU

ACGUGGUUA

GUUAAAAUC

CUGUGACUU

UGUGACLUU

CUUUGGCUU

CCCGGGAUA

CGGGAUAUU

GGGAUAUULJ

GGAUAUUA

CUGACCUU.

GGAGCAUC

UCAUCUGU

AUCUGUUA

UGUUACAG

ACAGCUUC

CAGCUTUCC

CCAAGUGG

CAAGUGGC

AGGGCAUG

CUUGGCAU

tJUGGCAUC

GGCAUCGC

GCGAAAGU

UCCACAGG

CACAGGGA

UCCUCUUA

CUCUUTAUC

UUAUCGGA

AUCGGAGA

UCGGAGAA

GGAGAAGA

AAAAUCUG

AAAUCUGU

UGUGACUU

UGGCUUGG

GGCUUGGC

GGCCCGGG

UUUAUAAA

UAUAAAGA

AUAAAGAU

UAAAGAUC

a a a. a a a 3157 UGGAUCUU CUGAUGA X GAA AUAAAUAU AAUAAAGUC AUAULTUAUA AAGAUCCA a- 112 C C. C

C

C

C

3163 3169 3170 3174 3190 3195 3199 3200 3225 3226 3227 3228 3239 3246 3258 3263 3265 3266 3267 20 3273 3274 3275 3288 3290 3291 3292 3293 3296 3297 3304 3305 3307 3311

AUAAUCUG

UCUGACAU

UUCUGACA

CCUULU

AGGGAGGC

UUCAAAGG

CCAULTUCA

UCCAUUUC

CUGUCAAA

UCUGUCAA

CUCUGtJCA

ACUCUGUC

GGAUUGUG

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

CUGAUGA

GAA AUCUUUAU GAA AUCUGGAU GAA AAUCUGGA GAA ACAUAAUC GAA AGCAUCUC GAA AGGCGAGC GAA AGGGAGGC GAA AAGGGAGG GAA AUUIGUUUC GAA AAUUGULU GAA AAAUUtJGUU GAA AAAAUTUGU GAA ACACUCUG GAA AUUGUGUA GAA ACGUCACU GAA ACCAGACG GAA AGACCAGA GAA AAGACCAG GAA AAAGACCA GAA ACACCAAA GAA AACACCAA GAA AAACACCA GAA AUUUCCCA GAA AUAUUJCC GAA AAUAUUUC GAA AAAUALUU GAA AAAAUALU GAA AGGAAAAU GAA AAGGAAAA GAA AGCACCUA GAA AAGCACCU GAA AGAAGCAC GAA AUGGAGAA AUAAAGAUC CAGALUJAU.

AUCCAGAUTU AUGUCAGA UCCAGAUUA UGUCAGAA GAUUAUGUC AGAAAAGG GAGAUGCUC GCCUCCCU GCUCGCCUC CCLTUUGAA GCCUCCCUU UGAAAUGG CCUCCCUUU GAAAUGGA GAAACAAUU UUUGACAG AAACAAUUU tJUGACAGA AACAAUUUU UGACAGAG ACAAUUUUU GACAGAGU

CAGAGUGUA

UACACAAUC

AGUGACGUC

CGUCUGGUC

UCUGGUCUU

CUGGUCUUU

UGGUCUUUU

LUJUGGUGLTLJ

LTUGGUGtUU

UGGUGUUUU

UJGGGAAAUA

GGAAAUAUU

GAAAUAUUU

AAAUAUUU

AAUAUUTUUC

AUUUUCCUU

UtJUUCCUUA

UAGGUGCUU

AGGUGCUTUC

GUGCUUCtJC

UUCUCCAUA

CACAAUCC

CAGAGUGA

UGGUCUUU

UUUUGGUG

UUGGUGUU

UGGUGUUU

GGUGUUUU

LUJGCUGUG

UGCUGUGG

GCUGUGGG

UUTUUCCUTLJ

UTUCCUUAG

UCCUUAGG

CCUUAGGU

CUUAGGUG

AGGUGCU

GGUGCUUC

CUCCAUAU

UCCAUAUC

CAUAUCCU

UCCUGGGG

113 0* be 0 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 3529

UACCCCAG

UCAAUCUU

UCUUICAUC

GCCUACAA

CGCCUACA

UCGCCUAC

CAAUCGCC

CLTUCUUUC

CCUCAUUC

UGUAGUAU

GUGUAGUA

UGGUGUAG

UIJCUGGUG

UGGUCUGG

GGGUCUCU

ACUCUGAA

AACUCUGA

CAACUCUG

CCAACUCU

GUUCCACC

AUUUCCCA

GAUUUCCC

UUGCAAGA

GCUUGCAA

UAGCUUGC

CUGAGCAU

AUCCUGCU

GAACAAUG

GGAAGAAC

AUCGGAAG

UAUCGGAA

GAUAUCGG

UGAUAUCG

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 AUAUGGAG GAA ACCCCAGG GAA AUCUUUAC GAA AUUCUUCA GAA AAUUCUUC GAA AAAUUCUU GAA ACAAAALU GAA AUCGCCUA GAA AGUtJCCUU GAA AUCAGGGG GAA AAUCAGGG GAA AUAAUCAG GAA AGUAUAAU GAA ACAUUUCU GAA ACUGGGCU

GAA'ACGUGGGU

GAA AACGUGGG GAA AAACGUGG GAA AAAACGUG GAA ACUCUGAA GAA AUGULICCA GAA AAUGUUCC GAA AUUUCCCA GAA AGAUTUUCC GAA AGAGAUUU GAA AGCUtJGCA GAA AGCAUEJAG GAA AGUCUUUG GAA AUGUAGUC GAA ACAAUGUA GA A AACAAUGU GAA AGAACAAU GAA AAGAACAA

CUCCAUAUC

CCUGGGGUA

GUAAAGALU

UGAAGAAUEJ

GAAGAAUUU

AAGAAUUUU

AAUUUUGUA

UAGGCGALU

AAGGAACUA

CCCCUGAUU

CCCUGAUTUA

CUGAUUAUA

AUUAUACUA

AGAAAUGUA

AGCCCAGUC

ACCCACGULJ

CCCACGUUU

CCACGULUU

CACGUUTUUC

UUCAGAGLU

UGGAACAUU

GGAACALUU

UGGGAAAUC

GGAAAUCUC

AAAUCUCUU

UGCAAGCUA

CUAAUGCUC

CAAAGACUA

GACUACAUU

UACAUTUGUU

ACATJUGUUC

AUUGUUCLU

UUGUUTCLTUC

CUGGGGUA

AAGAUUGA

GAUGAAGA

UTUGUAGGC

UGUAGGCG

GUAGGCGA

GGCGAUUG

GAAAGAAG

GAAUGAGG

AUACUACA

UACUACAC

CUACACCA

CACCAGAA

CCAGACCA

AGAGACCC

LUCAGAGU

UCAGAGU

CAGAGUTUG

AGAGUUGG

GGUGGAAC

UGGGAAAU

GGGAAAUC

UCLTUGCAA

UUGCAAGC

GCAAGCUA

AUGCUCAG

AGCAGGAU

CAUTJGUUC

GUTUCUUCC

CUTUCCGAU

UTUCCGAUA

CCGAUAUC

CGAUAUCA

114 3534 GUCUCUGA CUGAUGA 0 0 *000 000...

S

*0 0 0 0000 00 0S S 00..

00 S 0 000 4 3536 3544 3545 3562 3563 3570 3572 3574 10 3580 3584 3591 3592 3593 3598 3615 3629 3630 3(i34 20 3635 3654 3658 3662 3664 3676 3702 3710 3711 3718 3720 3725 3726

AAGUCUCU

CAUGCUCA

CCAUGCUC

GAGUCCAG

AGAGUCCA

GGCAGAGA

UAGGCAGA

GGUAGGCA

AGGUGAGG

AAACAGGU

AUACAGGA

CAUACAGG

CCAUACAG

CUCCUCCA

GGGUCACA

CAUAAUGG

UCAUAAUG

GUTUGUCAU

UGUUGUCA

UACUGACU

CAGAUACU

UC.UGCAGA

GUJCUGCA

CLTUCGCU

AAUGUU

UAUCUUCA

AUAUCUUC

UAACGGGA

UCUAACGG

GUUCUTUCU

GGLTUCLTUC

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

AUCGGAAG

AUAUCGGA

AGUCUCUG

AAGUCUCU

AUCCUCUU

AAUCCUCU

AGUCCAGA

AGAGUCCA

AGAGAGUC

AGGCAGAG

AGGUAGGC

ACAGGUGA

AACAGGUG

AAACAGGtJ

ACAGGAAA

ACUUCCUC

AUUUGGGG

AAUTUUGGG

AUGGAAUtJ

AAUGGAAU

AUTUCCUGC

ACUGAUtJC

ACUGACUG

AUACUGAC

ACUGUTUCU

ACACUCAC

AUGUUUULJ

AAUGUUEJUJ

AUCUUCAA

AUAUCUUC

ACGGGAUA

AACGGGAIJ

CUUCCGAUA

UCCGAUAUC

CAGAGACUU

AGAGACUUU

AAGAGGAUtJ

AGAGGAUUC

UCUGGACUC

UGGACUCUC

GACUCUCUC

CUCUGCCUA

GCCUACCUC

UCACCUGUU

CACCUGUUU

ACCUGUUUC

UUUCCUGUA

GAGGAAGUA

CCC CAAAUU

CCCAAAUUC

AAUUCCAUU

AUUCCAUUA

GCAGGAAUC

GAAUCAGUC

CAGUCAGUA

GUCAGUAUC

AGAACAGUA

GUGAGUGUA

AAAAACAUU

AAAACAULU

UtJGAAGAUA

GAAGAUAUC

UAUCCCGUU

AUCCCGLTUA

UCAGAGAC

AGAGACUU

UGAGCAUG

GAGCAUGG

CUGGACUC

UGGACUCU

UCUCUGCC

UCUGCCUA

UGCCUACC

CCUCACCU

ACCUGUUUT

UCCUGUAU

CCUGUAUG

CUGUAUGG

UGGAGGAG

UGUGACCC

CCAUUAUG

CAUUAUGA

AUGACAAC

UGACAACA

AGUCAGUA

AGUAUCUG

UCUGCAGA

UGCAGAAC

AGCGAAAG

AAAACAUU

UGAAGAUA

GAAGAUAU

UCCCGUtJA

CCGLTAGA

AGAAGAAC

GAAGAACC

0 400006 0 S 0

S

3741 AUUACUUU CUGAUGA X GAA ACUUCUGG CAAGAAAUA CCAGAAGUA AAAGUAAU r 115 6 3747 3750 3778 3783 3784 3786 3791 3808 3809 3827 3828 3830 3832 3836 3838 3839 3840 3872 3881 20 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

AUTUCCACC

AUGCCACA

AGCCUUCA

UCUGGUUU

CGGACUGG

GAUAUCCG

CGGAGUGA

AUCGGAGU

UGUCAUCG

CACUGGAG

CCUCACUG

AGCULTUAA

CAGCUTUUA

UCAGCUUJ

AUCAGCUU-

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

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAA ACUUIJUAC GAA AUUACLUU GAA ACCACUGU GAA ACCAUACC GAA AACCAUAC GAA AGAACCAU GAA AGGCAAGA GAA AGUUUUCA GAA AAGUUUTUC GAA AUJEGGLU GAA AAUTUUGGU GAA AUAAUUUG GAA AGAUAALU GAA AUGGAGAU GAA AGAUGGAG GAA AAGAUGGA GAA AAAGAUGG GAA ACUCCCUG GAA AUGCCACA GAA AGCCUUCA GAA AGCCGCUIJ GAA ACUGGUAG GAA AUCCGGAC GAA AUAUCCGG GAA AGUGAUAU GAA ACACGGUG GAA AGUACACG GAA AGUtJCUGC GAA AAGUUCUG GAA AAAGTJUCU GAA AAAAGUTUC GAA AUCAGCUU GAA AUCUCUAU

GUAAAAGUA

AAAGUAAUC

ACAGUGGUA

GGUAUGGUU

GUAUGGUUC

AUGGUUCUJ

UCLTGCCUC

UGAAAACUU

GAAAACUUU

AACCAAAUUJ

ACCAAAUTUA

CAAAUUAUC

AAUUAUCUC

AUCUCCAUC

CUCCAUCUtJ

UCCAUCUUU

CCAUCUUUU

CAGGGAGUC

UGUGGCAUC

UGAAGGCUC

AAGCGGCUA

CUACCAGUC

GUCCGGAUA

CCGGAUAUC

AUAUCACUC

CACCGtJGUA

CGUGUACUC

GCAGAACUUJ

CAGAACUUtJ

AGAACUUUU

GAACUUUUA

AAGCUGAUA

AUAGAGAUU

AUCCCAGA

CCAGAUGA

UGGUTJCUU

CUUGCCUC

UUGCCUCA

GCCUCAGA

AGAAGAGC

UGGAAGAC

GGAAGACA

AUCUCCAU

UCUCCAUC

UCCAUCU

CAUCUUU

UUUUGGUG

UUGGUGGA

UGGUGGAA

GGUGGAAU

UGUGGCAU

UGAAGGCU

AAACCAGA

CCAGUCCG

CGGAUAUC

UCACUCCG

ACUCCGAU

CGAUGACA

CUCCAGUG

CAGUGAGG

UTUAAAGCU

UAAAGCUG

AAAGCUGA

AAGCUGAU

GAGAUTUGG

GGAGUGCA

a- 116 4006 GGCUGUGC CUGAUGA X GAA ACCGGUUU AAACCGGUA GCACAGCC 4020 4021 4023 4052 4054 4057 4062 4063 4064 4076 4089 4098 4110 4115 4120 4121 4122 4130 20 4133 4134 4136 4137 4138 4153 4161 4162 4166 4167 4168 4169 4172 4173

GGCUGGAC

AGGCUGGD

UCAGGCUC

CAGGAGGP.

AACAGGAG

UTUAAACAG

UCCUUUUA

LU~CCUUUU

CUUICCUTJU

GGGGUGUG

AUGUCCGG

UCUCAUGU

UCUGAGCA

CAAAAUCU

CACUTUCAA

ACACIJUCA

AACACUTUC

GAAAGAAC

GUGGAAAG

GGUGGAAA

CUGGUGGA

GCUGGUGG

UGCUGGUG

AAUGCGGC

GAAAAUCA

UGAAAAUC

GAAAUGAA

CGAAAUGA

UCGAAAUG

GUCGAAAU

GUUTGUCGA

UGLTUGUCG

;CUGAUGA

LCUGAUGA

CUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

C'UGAUGCA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA 2 CUGAUGA2

CUGAUGA)

GAA AUCUGGGC GAA AAUCUGGG *GAA AGAAUCUG *GAA AGCUCAGU GAA AGAGCUCA GAA AGGAGAGC GAA ACAGGAGG GAA AACAGGAG GAA AAACAGGA GAA AUGCUUCC GAA AGUTUGGGG GAA AUGUCCGG GAA ACCUCUCA GAA AGCAGACC GAA AUCUGAGC GAA AAUCUGAG GAA AAAUCUGA GAA ACACUtJCA 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 GAA AAUGAAAA

GCCCAGAUJ

CCCAGAUUC

CAGAUUTCUC

ACUGAGCUC

UGAGOUCUC

GCUCUCCUC

CCUCCUGUU

CUCCUGUUU

UCCUGUUUA

GGAAGCAUC

CCCCAACUC

CCGGACAUC

UGAGAGGUC

GGUCUGCUC

GCUCAGAU

CUCAGAUUU

UCAGAUUUtJ

UGAAGUGTLJ

AGUGUUtGUU

GUGUUGUUC

GUUGUUCUU

UUGUUCUULJ

UGUTUCUUUC

CAGGAAGUA

AGCCGCAUU

GCCGCAUUU

CAUUUGAUUJ

AUUtJGAUU

UTUUGAUUUU

UUGAUUUUC

AUUJIUCAUU

UUUTUCAULU

FCUCCAGCC

UCCAGCCU

CAGCCUGA

UCCUCCUG

CUCCUGUUI

CUGUTUUAA

UAAAAGGA

AAAAGGAA

AAAGGAAG

CACACCCC

CCGGACAU

ACAUGAGA

UGCUCAGA

AGAUUUUG

UUGAAGUG

UGAAGUGU

GAAGUGLU

GUTUCUUTUC

CUUUCCAC

UUCCACC

UCCACCAG

CCACCAGC

CACCAGCA

GCCGCAUU

UGAUUUC

GAUUUUCA

UUCAULUJC

UCAUUUCG

CAUUUCGA

AUUUCGAC

UCGACAAC

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 UJUCAUUUC GACAACAG AAGGACCUC GGACUGCA AGCCAGCUC UUCUAGGC CCAGCUCUU CUAGGCUU CAGCUCUtJC UAGGCUUG GCUCUUCUA GGCUUGUG 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.

S.

S

S. S

*S*

S S S *5

S

S S S S S *5 S 5* .5 5 *5 S S S S S S S S S 55 5 5 5*S

S

118 Table V: Human KDR VEGF Recentor-Hairpin Ribozvme and Substrate Seauences nt.

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

CGACGGCC

CACAGGGC

CCCACAGA

UGAGCCUG

GAGGCCAA

AAAUGGAG

CUGUUACC

ACAUAAUA

IJUCCAUGA

UuUUCUCC

CACUCCCA

UCUUGGUC

CCAUAAUC

UCUCACCA

AUGGCAUA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCACCU

GCCAGC

GCCCGG

GAUCAA

GUUUCC

GUAAtJC

GGAACA

GGUAAC

GACUCA

GAUAGU

GGGUUU

GCCCAC

GUACAU

GGGGUG

GUACAU

ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUTGUGGUACAUJTACCUGGUA.

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGki&AAACACACGUUGUGGUACAUJ1ACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUUrACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUYACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUrJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

AGGUGCU

GCUGGCC

CCGGGCC

IJUGAUCU

GGAAACU

GATJUACA

UGUUCCU

GUUACCA

UGAGUCC

ACUAUCU

AAACCCA

GUGGGCU

AUGUACU

CAC CC CA

AUGUACG

GCU

GtJC

GCC

G.CC

GAC

GAU

GAU

GUC

GUC

GUU

GUC

GAU

GAC

GAU

GUC

GGCCGUCG

GCCCUGUG

UCUGUGGG

CAGGCUCA

UUGGCCUC

CUCCAUUU

GGUAACAG

CO

UAUUAUGU

UCAUGGAA

GGAGAAAA

UGGGAGUG

GACCAAGA

GAUTJAUGG

UGGUGAGA

UAUGCCAU

119 1376 CU!JCCUCC AGAA GCCAAU ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA AUUGGCA GUU GGAGGAAG 1413 1569 1673 1717 1760 1797 1918 1967 1974 2021 2084 2418 2453 2492 2547 2765 2914

GUCACUGA

UUGUACAA

GCUCAGUG

AAACGUAG

UUGGCAGA

UUCIJUGCA

UUGAGCAA

GGACUGUG

CGCUCUAG

UACUUJGUC

ACCACAUG

GGGAGUUC

CAUCAUAA

CUAGGUUC

CCAAAGGC

GGUAAGUG

AAAUCCAG

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GC!JUGG

GACACA

GCAUGU

GUCUGC

GUGGGC

GGUGUG

GACAUA

GCCUGA

GUGAGC

GAUUCU

GUGGAG

GGAUCC

GUCGUU

GGUCUC

GCUUCA

GGUUUC

GGCUGA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUtACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGIJUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAIJUACCUGGUA

CCAAGCU

UGUGUCA

ACAUGCA

GCAGACA

GCCCACA

CACACCU

UAUGUCU

UCAGGCA

GCUCACA

AGAAUCA

CUCCACA

GGAUCCA

AACGACU

GAGACCG

UGAAGCA

GAAACCU

UCAGCCA

GUC

GCU

GCC

GAU

GCC

GUU

GCC

GCU

GUC

GAC

GAU

GAU

GCC

GCU

GAU

GUC

GCU

UCAGUGAC

UUGUACAA

CACUGAGC

CUACGIUUU

UCUGCCAA

UGCAAGAA

UTUGCUCAA

CACAGUCC

CUAGAGCG

GACAAGUA

CAUGUGGU

GAACUCCC

UUAUGAUG

GAACCUAG

GCCUUUGG

CACUUACC

CUGGAIUU

2993 293 GCUCCAAG AGAA GGAAGU ACCAGAGAAACACACGUUGUGGUACATJUACCUGGUA AUCUGCCUGG ACUUCCU GAC CUUGGAGC S. S S. S S S S S S S S S S 120 3019 3165 3378 3404 3418 3575 3588 3689 3753 3764 3911 3927 4011 4016 4025 4059 4111 4116 4195 CACUTJGGA AGAA GUAACA ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA UGUUACA GCTJ UCCAAGUG I,

CUGACAUA

GUAGUAUA

CCAGCAUG

CCCGUGCC

GUGAGGUA

AUACAGGA

CACUCACA

UGGUUGUC

CACUGUCC

GAUAUCCG

UCUGUGUC

AGAAUCUG

GCUGGAGA

CCGUGUCA

UCCUIJUUA

AAAAUCUG

ACUUCAAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GGAUCU

GGGGCC

GGUACA

GUCCAG

GAGAGA

GGUGAG

GGCUCU

GGGAUU

GGUUGU

GGUAGC

GAGUGA

GUGCUA

GGGCUG

GGAGAA

GGAGGA

GACCUC

GAGCAG

ACCAGAGAAACACACGTJUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGtJUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGJA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUrJGUGGUACAUIJACCUGGUA

AGAUCCA

GGCCCCU

UGUACCA

CUGGACU

UCUCUCU

CUCACCU

AGAGCCG

AAUCCCA

ACAACCA

GCUACCA

UCACUCC

UAGCACA

CAGCCCA

UUCUCCA

UCCUCCU

GAGGUCU

CUGCUCA

GAU

GAU

GAC

GCU

GCC

GUU

GCC

GAU

GAC

GUC

GAU

GCC

GAU

GCC

GUU

GCU

GAU

UAUGUCAG

UAUACUAC

CAUGCUGG

GGCACGGG

UACCUCAC

UCCUGUAU

UGUGAGUG

GACAACCA

N)

0D

GGACAGUG

CGGAUAUC

GACACAGA

CAGALTUCU

UCUCCAGC

UGACACGG

UAAAAGGA

CAGAUUUU

UTUUGAAGU

UCCCUGCA AGAA GAGGUC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GCUGGCUCGG GACCUCG GAC UGCAGGGA S *5

S.

S. S S. *5 55 S.

S S S S S S S S S. S S 555 121 4210 CCUAGAAG AGAA GGCUCC ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GGAGCCA GCU CUUCUAGG ~1

I'

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

Posi tion HH. Ribozymne Sequence Substrate 13 18 31 37 44 46 59 61 66 67 83 97 114 115 169 171 178 180 197 204 212 213 215

CCGUACCC

GGGIJCCCG

UCGACCUC

AUACCGUC

CUTUAUCGA

AGCUTJAUC

AUCAAGCU

UCGAUAJC

GAAUUCGA

CCGAAUTUC

UGGGCCCG

CUGGGCCC

GGCUGCGG

AGCCAGGU

GUCCGCGG

UGUCCGCG

ACCGGGGA

AGACCGGG

CAGCGCAA

CGCAGCGC

AGAGGCGG

AAGUCACA

CCGCAAAG

CCCGCAAA

GGCCCGCA

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 ATJUCGCCC GAA ACCCAAU GAA AGGGGGGU GAA ACCUCGAG GAA ACCGUCGA GAA AUACCGUC GAA AUCGAUAC GAA AGCUJEAUC GAA AUCAAGCU GAA AUAUCAAG GAA AUUCGAUA GAA AAUTUCGAU GAA ACACAGUC GAA AUCCCGGC GAA AUCGGGUC GAA AAUCGGGU GAA AGCGCGGG GAA AGAGCGCG GAA ACCGGGGA GAA AGACCGGG GAA AUGGCCCC GAA AGGCGGUA GAA AGtJCACAG GAA AAGUCACA GAA AGAAGUCA GGGCGAALTTJ GGGTJACGG AALTJGGGUA CGGGACCC ACCCCCCUC GAGGUCGA CUCGAGGUC GACGGUAU UCGACGGtJA UCGAUAAG GACGGUAUC GAUAAGCU GUAUCGAUA AGCUUTGAU GAUAAGCUUJ GAUAUCGA AGCUIJGAUA IJCGAAUUC CUTUGAUAUC GAAUTUCGG UAUCGAAIJU CGGGCCCA AUCGAAtJUC GGGCCCAG GACUGUGUC CCGCAGCC GCCGGGAUA ACCUGGCU GACCCGAUJT CCGCGGAC ACCCGAUtJC CGCGGACA CCCGCGCUC UCCCCGGU CGCGCUCUC CCCGGtJCU UCCCCGGUC UUGCGCUG CCCGGUCUU GCGCUGCG GGGGCCAUA CCGCCUCU UACCGCCUC UGUGACUU CUGUGACUTJ CUtJUGCGG UGUGACUUC UUUGCGGG UGACUUCUU UGCGGGCC 123

S.

S

S

S. S

S

S 55 S 55

S

SSSSSS

S

216 241 262 306 312 316 323 324 347 10 355 356 367 368 369 370 372 376 387 405 414 415 416 424 432 433 438 439 442 471 472

UGGCCCGC

CAGGCACA

UGGGCACA

GCGACAGC

CACAGAGC

GAACCACA

CCACGCAG

UCCACGCA

AACCCACA

GCCAGUCA

CGCCAGUC

AtJGGAGAA

GAUGGAGA

GGAUGGAG

GGGAUGGA

GGGGGAUG

CUUGGGGG

UGUGUGCU

AUUGUCAG

UTUUGCCAA

AUUUGCCA

UAUUUtGCC

AAGGGUIJG

GUAAUCUG

AGUAAUCU

CUGCAAGU

CCUGCAAG

UCCCCUGC

LJGGGCCA

ALTUGGGCC

CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGATJGA X CUGAUGA X CUGAUGA X CUGAU.GA X CUGAULGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAIJGA X CUGAUGA X CUGAtJGA X CUGAUGA X CUGAUGA X CUGAUGA X UGAUGA X -UGAUGA X 7UGAUGA 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 AGCUUGGG GAA AUGUCUUU GAA AtJUGUCAG GAA AAUUGUCA GAA AAAUUQ.UC GAA AUUUGCCA GAA AGGGUUGU GAA AAGGGUUG GAA AUCUGAAG 7AA AAUCtJGAA 3AA AGUAAUCU 3AA AGCCAGUC 3AA AAGCCAGU GACTJICUTJU

GCGGGCCA

GAAGGAGUC

UGUGCCUG

ACUGGGCUC

UGUGCCCA

GCGCUGCUA

GCUGUCGC

CIJAGCUGUC GCUCUGUG CtJGUCGCUC

UGUGGIJUC

UCUGTJGGTJU CUGCGUGG CUGUGGUIJC UGCGUGGA AGCCGCCUC UGUGGGUU CUGUGGGUU UGACUGGC UGUGGGUUtJ GACIJGGCG CUGGCGAUU UtJCUCCAU UGGCGAUUU TJCUCCAtJC GGCGATJUUU CUCCAUCC GCGAUUtJEC UCCAUCCC GAUUUEJCUC CAUCCCCC UUCUCCAUC CCCCCAAG CCCAAGCUC AGCACACA AAAGACAUA CUGACAAU CUGACAAUU UUGGCAAA UGACAAIJUU UGGCAAAU GACAAUUEJU GGCAAAUA UGGCAAAUA CAACCCUEJ ACAACCCUTU CAGAUTUAC CAACCCUUC AGAUtJACU CUUCAGALTU ACULJGCAG TJUCAGAUJUA CLTLJG CAGG AGAUUACUU GCAGGGGA GACUGGCUU UGGCCCAA ACUGGCUUU GGCCCAAU 124 484 AUCACGCU CUGAUGA X GAA AGCAUUGG p 493 494 507 '5509 538 540 542 543 10 555 56).

562 573 583 593 602 605 615 621 626 633 634 635 639 641 645 646 652 653

ULJCCUCAG

UtJUCCUCA

GTJCACCAA

CAGUCACC

GCAGAAGA

UTJGCAGAA

UUUUGCAG

GUUUEJGCA

GGAAUGGU

ACCCUGGG

CACCCUGG

UCALUUCC

GGCUCCAG

AGCACUUTG

CCCGGUAC

CGUCCCGG

GCUAUGUC

GUGGAGGC

AAACAGUG

UAGACAUA

AUAGACAU

CAUAGACA

CGAACAUA

CUCGAACA

UAAUCtJCG GUAAUCtJC

UGAUCIJGU

GUGAUCUGC

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 CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X UGAUGA X 2UGAUGA X -UGAUGA X =GAUGA X 'TGAUGA XC UTGAUGA XC .UGAUGA X GAA AUCACGCU GAA AAUCACGC GAA ACCCUUITJC GAA AUACCCU GAA ACUGUCAC GAP. AUACUGUC GAP. AGAUACUG GAP. AP.GAUACU GAP. AGUGUUUUT GAP. AUGGUGAG GAP. AP.UGGUGA GAA ACCACCCU GAP. AUCAUULUC GA. AGGCUCCA GAP. AGCACUUTG GAP. ACGAGCAC GAP. ACGUCCCG GAP. AUGUCGAC 3AP. AGGCUAUG 3AA ACAGUGGA 7AP. AACAGUGG AA. AAP.CAGUG ,AA. ACAUAAAC 'AA AGACAUA.

'AA ACAUAGAC 'AA AP.CAUAGA ;AP. AUCUCGAA YAA AAUCUCGA CCAAUGCUC AGCGUGAU AGCGUGAUU

CUGAGGAA

GCGUGAUUC

UGAGGAAA

GAAAGGGUA

UUGGUGAC

AAGGGUAUU GGUGACTJG GUGACAGUP.

UCUUCUGC

GACAGUAUC

UTJCUGCAA

CP.GUAUCUU CUGCAAAA AGUAIJCUUC

UGCAAAAC

AAAPACACUC ACCAUtJCC CUCACCAIJEJ CCCAGGGU UCACCATUC

CCAGGGUG

AGGGJGGUUt GGAAAUGA GAAAUGAUA

CUGGAGCC

UGGAGCCUA CAAGUGCU CAAGUGCUC

GUACCGGG

GUGCUCGUA

CCGGGACG

CGGGACGUC

GACATJAGC

GUCGACAUA GCCIJCCAC CAUAGCCUC CACUGLUU UCCACUGUU UAUGUCUA CCACUGUUTJ AUGUCUAU CACUGUtUtA

UGUCIJAUG

GUEJUAUGUC UAtJGUUCG.

UUAUGUCUA

UGUUCGAG

GUCUAUGUTU CGAGAUTUA UCUAUGUUC

GAGAUUAC

UUtCGAGAULJ

ACAGAUCA

UCGAGAULTJA

CAGAUCAC

UUTACAGAUC ACCAUTUCA 659 UGAAUGGU CUGAUGA X GAP. AUCUGUAP.

125 665 AGGCGAUG CUGAUGA X GAA AUGGUGAU 666 GAGGCGAU CIJGAUGA X GAA AAUGGIJGA 0 0 00** 0**000 0 00.0..

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

ACAGAGGC

CACUGACA

UGGUCACU

AUGUACAC

CGGUGAUG

UTUCUCGGU

CGGCAGGG

UGAAAUC

AGGIJUUGA

GAGGUUG

UGAGGUUU

GACACAUU

CGCAAAGA

AGCGCAAA

CUAGCGCA

CCUAGCGC

UGGAUACC

UTUUCUGGA

CUTJUUCUG

CCGGAACA

UCCGGAAC

CCAUCCGG

UCCAUCCG

UCCCAGGA

GUCCCAGG

UGUCCCAG

GUAAAGCC

GGAGAGUAC

CUGAUGA X GAA AUGAAUGG CUGAUGA X GAA AGGCGAUG CUGAUGA X GAA ACAGAGGC CUGAUGA X GAA AUG CCAUG CUGAUGA X GAA ACACGAUG CUGAUGA X GAA AUGUACAC CUGAUGA X GAA AUCACCAC CUGAUGA X GAA ACCCUCGG CUGAUGA X GAA AUCGACCC CUGAUGA X GAA AAUCGACC CUGAUGA X GAA AAAUCGAC CUGAUGA X GAA AGGUUUGA CUGAUGA X GAA ACACAUTUG CUGAUGA X GAA AGACACAU CUGAUGA X GAA AGAGACAC CUGAUGA X GAA AAGAGACA CUGAUGA X GAA AGCGCAAA CUGAUGA X GAA ACCUAGCG CUGAUGA X GAA AUACCUAG CUGAUGA X GAA AUCUCUUU CUGAUGA X GAA AAUCUCUU CUGAUGA X GAA ACAAAUCU CUGAUGA X GAA AACAAAtJC -UGAUGA X GAA AUUCUGUU 7UGAUGA X GAA AAUTUCUGU UGAUGA X GAA AAAUUCUG UGAUGA X GAA AUCUCGCU 'UGAUGA X GAA AGCCUAUC AUCACCAUU

CAUCGCCU

UCACCAUU.C

AUCGCCUC

CCAUTUCAUC

GCCUCUGU

CAUCGCCUC

UGUCAGUG

GCCtJCUGtJC

AGUGACCA

CAUGGCAUC

GUGUACAU

CAUCGUGIJA

CAUCACCG

GTJGUACAUC

ACCGAGAA

GUGGUGAUC

CCCUGCCG

CCGAGGGUC

GAUUUTCAA

GGGUCGAUU

UCAAACCU

GGUCGAUUIJ

CAAACCUC

GUCGAtUUJC

AAACCUCA

UCAAACCUC

AAUGUGUC

CAAUGUGUC

UCUUUGCG

AUGUGUCUC

UUUGCGCU

GUGUCUCTJU UGCGCUAG UGUCUCIJUU

GCGCTJAGG

UUUGCGCUA GGUAUCCA CGCUAGGUA UCCAGAAA CUAGGUAUC CAGAAAAG AAAGAGAUU

UGUUCCGG

AAGAGAUUU

GUUCCGGA

AGAUUJUGUU CCGGAUGG GAUtJUGUTJC

CGGAUGGA

AACAGAAUU UCCUGGGA ACAGAAUUU

CCUGGGAC

CAGAAUUUC

CUGGGACA

AGCGAGAUA

GGCUUUAC

GAUAGGCUU UACUCUCC 126 a a 846 847 850 852 859 860 867 872 885 10 887 888 903 917 919 923 925 927 932.

936 939 945 948 953 955 960 961 962 972 973 993

GGGAGAGU

GGGGAGAG

ACUGGGGA

UAACUGGG

GAUCAUGU

UGAIJCAUG

GCAUAGCU

UGCCGGCA

UCACAGAA

CCUCACAG

GCCUCACA

UCAUCAUU

UAGACUGA

GAtJAGACU

ACAUGAUA

GUACAUGA

AUGUACAU

CAACUAUG

ACCACAAC

ACAACCAC

UAUCCUAC

CUAUAUCC

AAAUCCUAC

AUAAAUCCC

ACAUCAUA C CACAUCAU C UCACAUCA C

GGGCUCAGC

GGGGCUCAC

GAUAGCUC C CUGAUGA X GAA AAGCCUAU CUGAUGA X GAA AAAGCCUA CUGAUGA X GAA AGUAAAGC CUGAUGA X GAA AGAGUAAA CUGAUGA X GAA ACUGGGGA CUGAUGA X GAA AACUGGGG CUGAUGA X GAA AUCAUGUA CUGAUGA X GAA ACCUGAUC CUGAUGA X GAA ACCAUGCC CUGAUGA X GAA AGACCATJG CUGAUGA X GAA AAGACCAU CUGAUGA X GAA AUCUUtJGC CUGAUGA X GAA AGGUTJUCA CUGAUGA X GAA AUAGGUUU CUGAUGA X GAA ACUGAUAG CUGAUGA X GAA AGACUGAU CUGAUGA X GAA AUAGACUG 2UGAUGA X GAA ACAUGAUA CUGAUGA X GAA AUGUACAU UGAUGA X GAA ACUAUGUA "UGAUGA X GAA ACCACAAC :UGAUGA X GAA ACAACCAC UGAUGA X GAA AUCCUACA :UGAUGA X GAA AUATJCCtJA UGAUGA X GAA AUCCTJAUA ~UGAUGA X GAA AAUCCUAU ~UGAUGA X GAA AAAUCCUA ,TUGAUGA X GAA AUCACAUC 'UJGAUGA X GAA AAUCACAU :UGAUGA X GAA AUUUECAUG AUAGGCUIJU ACUCUCCC UAGGCUUJUA CUCUCCCC GCUUIJACUC TJCCCCAGU UUUACUCUC

CCCAGUUA

UCCCCAGUU ACAUGAUC CCC CAGUTUA CAUGAUCA UACAUGAUC

AGCUAUGC

GAUCAGCtJA UGCCGGCA GGCAUGGtJC UUCUGUGA CAUGGUCUU CUGUGAGG AUGGUCUtJC UGtJGAGGC GCAAAGAUC AAUGAUGA UGAAACCUA UCAGtJCUA AAACCUAUC AGUCUAtJC CUAUCAGUC IJAUCAUGU AUCAGUCUA UCAUGUAC CAGUCUAUC AUGUACAU UAUCAUGUA CAUAGUEJG AUGUACAUA

GUUGUGGU

UACAUAGUIJ GUGGUTUGU GUIJGUGGUU GUAGGAUA GUGGUUGUA GGAUAUAG UGUAGGAUA UAGGAUTU UAGGAUAUA GGAULUAU UAUAGGAUU UAUGAUGU AUAGGAUUU AUGAUGUG UAGGAUtJUA UGAUGUGA GAUGUGAUU CUGAGCCC AUGUGAUUC

UGAGCCCC

CAUGAAAUTU GAG CUAUC S S

S

Sosa

S

4s** 127 999 1001 1017 10.20 1022 1023 1027 1030 1047 1059 1063 1064 1065 1076 1078 1084 1085 1091 1093 1096 1099 1107 1110 1130 1131 1132 1154 1155 1156

CCGGCAGA

CUCCGGCA

UUUAAGAC

CAAUTUUAA

UACAALTJLJ

GUACAALU

CGCUGUAC

UCUCGCUG

CCCACAU1J

GUGAAAUC

CCAGGUGA

GCCAGGUG

UGCCAGGU

AAGGUGGA

UGAAGGUG

AGACUUUG

GAGACUUtJ

UAUGAUGA

CUUAUGAU

CUUCUUAU4

AAUCUUCU

CGGUUUAC4

UCCCGGLU

UCCCAGGA

GUCCCAGG

AGUCCCAG

UGCUCAAA

GUGCUCAA

GGUGCUCA

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 =UAUGA X 7UGAUGA X 7UGAUGA X 7UGAUGA X UGAUGA X UGAUGA X GAA AGCUCAAU GAA AUAGCUCA GAA AGULULUJC GAA ACAAGUUUJ GAA AGACAAGU GAA AAGACAAG GAA-- AUTLtJAAGA GAA ACAAUUTJA GAA AGCUCUGU GAA AGCCCCAC GAA AUCAAGCC GAA AAUCAAGC GAA AAAUCAAG GAA AGUGCCAG GAA AGAGUGCC GAA AGGUGGAG GAA AAGGUGGA GAA ACUUtJGAA GAA AGACUUtJG GAA AUGAGACU GAA AUGAUGAG GAA AUCUTJCUU GAA ACAAUCUU GAA AGGGUUUC GAA AAGGGULTJ GAA AAAGGGUU GAA ACAUCUUIC GAA AACAUCUU GAA AAACAUCU AUtJGAGCUA UCUGCCGG UGAGCUAUC UGCCGGAG GAAAAACUU GUCUUTAAA AAACUUGUC

UUAAAUUG

ACUUGUCUU AAAuuGUA CUUGUCUUA AAUUGUAC UCUUAAAtJU

GUACAGCG

UAAAUUGUA CAGCGAGA ACAGAGCUC

AAUGUGGG

GUGGGGCULJ GAUJIUCAC GGCUUGAUtJ UCACCUGG GCUUGAUUU CACCUGGC CUUGAUUUC ACCUGGCA CUGGCACUC UCCACCUU GGCACUCUC

CACCUUCA

CUCCACCUU CAAAGUCU UCCACCUUC

AAAGUCUC

UUCAAAGUC UCAUCAUA CAAAGUCUC AUCAUAAG AGUCUCAUC AUAAGAAG CUCAUCAUA AGAAGAUU AAGAAGAUILJ

GUAAACCG

AAGAUUGUA AACCGGGA GAAACCCUU UCCUGGGA AAACCCUUU CCUGGGAC AACCCUUUC CUGGGACU GAAGAUGUU UUTUGAGCA AAGAUGUTUU UUGAGCAC AGAUGUUTJU UGAGCACC GAUGUUUUU GAGCACCU 1157 AGGUGCUC CUGAUGA X GAA AAAACAUC 128 9*aa a 1166 1173 1205 1215 1220 1236 1246 1253 1254 1257 1263 1264 1276 1277 15 1278 1279 1281 1285 1286 1287 1291 1304 1306 1307C 1330 t 1335C 1341t 1352 1354 G

CUGGACGC

GUCCACJG

TJTUCUCUU

AAAJGUJC

CUCGGACA

ACUCGGAC

UGAACTJCG.

UUTJGUGUG

CULUJGUGU

AGCAAUAA

AAGCAATJA

AAAGCAAU

GAAAGCAA

CCGAAAGC

PCUACCGA

CACUACCG

CCACUACC

ZAUCCCAC

MCACCAAA

JUCCACCA

.'=tCCACC C JCGGACUtJ C

;GGATLJCGC

JTUCACAGG C

LACUGAGAC

UtAACUGA C

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA CUGAUGA CUGAUGA Y~ CUGAUGA X~ CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X =UAUGA X MUGAUGA x IJGAUGA X .UGAUGA X ~UGAUGA X UGAUGA X .TJGAUGA X UGAUGA X UEGAUGA X UJGAUGA X CUAUUGUC CUGAUGA ACACIJUUC CUGAUGA

CACAGGUG'CUGAUGA:

X GAA AGGUGCUC X GAA AUUGUCAA X GAA AUUCCCCU X GAA ACACAGGU K GAA ACGCUACA ,K GAA AUCAUCCG (GAA ATJUUCUCU C GAA AUGUUCUA GAA AAUGUUTCU GAA ACAAAUGU GAA ACUCGGAC GAA AACUCGGA GAA AGGCUUUG GAA AAGGCUUUL GAA AAAGGCLU GAA AAAAGGCU GAA AUAAAAGG GAA AGCAAUAA GAA AAGCAAIJA GAA AAAGCAAU GAA ACCGAAAG GAA AUTUUCAUC GAA AGAUUUCA GAA AAGALtUUC GAA ACUGCCCA GAA ACUUtGACU GAA AUUCGGAC GAA ACUUCACA GAA AIJACUUCA GAG CACCUU GACAAUAG UUGACAAUA

GAAAGUGU.

AGGGGAAUA CACCUGUiG ACCUGUGUA

GCGUCCAG

UGUAGCGUC

CAGUGGAC

CGGAUGAUC

AAGAGAAA

AGAGAAAUA

GAACAUUJ

UAGAACAUTU

UGUCCGAG

AGAACAUUU

GUCCGAGU

ACAUULJGIC

CGAGUUCA

GUCCGAGUU

CACACAAA

UCCGAGUUC

ACACAAAG

CAAAGCCUU

TJUAUUTGCU

AAAGCCUTUU

UAUUTGCIJU

AAGCCIJUUU

AUUGCUUU

AGCCtUUUA UUGCtJUUC CCUUUULALTU

GCUUIJUCGG

tJUAUUGCUU

UCGGIJAGU

UAUUGCUUUI

CGGTJAGUG

AUUGCUtJUC

GGUAGUGG

CtJUUCGGUA

GUGGGAUG

GAUGAAAUC

UUIJGGUGG

UGAAAIJCUU

UGGUGGAA

GAAAUCULUU

GGUGGAAG

UGGGCAGUC

AAGUCCGA

AGUCAAGUC

CGAAUCCC

GUCCGAAUC

CCUGUGAA

UGUGAAGUA

UCUCAGUU

UGAAGUAUC

UCAGUUAC

AAGUAUCUC AGUUACCC 1356 GGGUAACU CUGAUGA X GAA AGAUACUj 129 1360 AGCUGGGU CLJGAUGA X GAA ACUGAGAU a 1361 1369 1375 1377 1385 1404 1409 1415 1425 1428 1440 1446 1478 1485 1488 1491 1503 1504 15051 1530 1532 1534 15392 1548t 1560t 1574 C 1578 1580 C

GAGCUGGG

GAUAUCAG

CCAIUUGA

UACCALUU

CAUUIUCUG

UTJGGACUC

UGTJAGUUG

UCAUTJGUG

UCGCCAAC

UCAUCGCC

AUGAUGGU

ACUUCCAU

UGACCGUG

GUGAGGAU

UUGGUGAG

GGGUUGGU

LJCCAUTUGA

CTJCCAUEJG

UJCUCCATL

kCCAGAGA

AACCAGA

:ACAACCAC

kCAUUCACC

JGGGGUGGC

JTJCUCACCC

CGAGAUC C

LUAGGCGAC

CAtJAGGCC CTJGAUGA X GAA AACUGAGA CUGAtJGA X GAA AGCUGGGU CUGAUGA X GAA AUCAGGAG CUGAUGA X GAA AUAUCAGG CUGAUGA X GAA ACCAUUUG CUGAUGA X GAA AUGGGCCU CUGAUGA X GAA ACUCAAUG CUGAUGA X GAA AGUUGGAC CUGAUGA X GAA AUCAUUGU CUGAUGA X GAA ACAAUCAU CUGAUGA X GAA AGUIJCAUC CUGAUGA X GAA AUGGUGAG CUGAUGA X GAA AGUTUUCCU CUGAUGA X GAA ACCGUGUA CUGAUGA X GAA AUGACCGU CUGAUGA X GAA AGGAUGAC CUGAUGA X GAA AUGGGGUU CUGAUGA X GAA AAUGGGGU CUGAUGA X GAA AAAUGGGG -UGAUGA X GAA ACCAUGUG UGAUGA X GAA AGACCAUG :UGAUGA X GAA AGAGACCA UGAUGA X GAA ACCAGAGA UTGAUGA X GAA ACAUUCAC UTGAUGA X GAA AUCUGGGG UGAUGA X GAA AGGCUTUUC UTGAUGA X GAA AUCAAGGC 'UGAUGA X GAA AGAUCAAG AUCUCAGUU

ACCCAGCU

UCUCAGUUA

CCCAGCUC

ACCCAGCUC

CUGAUAUC

CUCCUGAUA

UCAAAUGG

CCUGAUAUC

AAAUGGUA

CAAAUGGUA

CAGAAAUG

AGGCCCAUU

GAGUCCAA

CAtJUGAGUC

CAACUACA

GUCCAACUA CACAAUGA ACAAUGAUU

GUUGGCGA

AUGAUUGUU

GGCGAUGA

GAUGAACUC

ACCAUCAU

CUCACCAUC

AUGGAAGU

AGGAAACUA

CACGGUCA

UACACGGUC

AUCCUCAC

ACGGUCAUC

CUCACCAA

GUCAUCCUC

ACCAACCC

AACCCCAUU

UCAAUGGA

ACCCCAUUU

CAAUGGAG

CCCCAUJUC

AAUGGAGA

CACAUGGUC UCUCUGGU CAUGGUCUC

UCUGGUTUG

UGGUCUCUC

UGGUUGUG

UCUCUGGUU

GUGAAUGU

GUGAAUGUC

CCACCCCA

CCCCAGAUC GGU'GAGAA GAAAGCCUU

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 1667 1677 1691 1694 1718 1723 1726 1750 1751 1752 1770 1776 1790 1800 1821 1825 1833 1836 1853

ACUGGUAG

CAUACUGG

UGGUCCCA

UGCAUGUC

UUGGCGUA

GGUTJGGCG

GUGCAGGG

UACCACUG

GCUGCCAG

GCUTUCUULC

GUCtIGUAG

CGGGUCUG

UACAAGCA

LTUCUtJUAC

CCAUUCUJ

CCCCUGGA

CCCCCUGG

CCCCCCUG

GUGACIJUC

LUUUtGGUC

UCAGGGCA

UUUCCUrjCc

.GCGUACUC

GACCAGCG C 3CUUGGAUC 3CAGCUUGC %.CAACGCU C CtJGAUGA:

CUGAUGA:

CUGAUGA

CtJGAUGA:

CUGAUGA

CUGAUGA CUGAUGA CUGAUGA CUGAUGA Y CUGAUGA X CUGAUGA X~ CIJGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X UGAUGA X MUGAUGA X MUGAUGA X 'TUGAUGA X ~UGAUGA X UTGAUGA X UGAUGA X UTGAUGA X .UGAUGA X UGAUGA X X GAA AAUCCAUA K GAA AGGAAUCC K GAA ACUGGUAG GAA AUGUCUGC C GAA ACUGUGCA CGAA AGACUGUG GAA AGGGUUGG GAA AUGUGGUG GAA ACCACUGG GAA AGCUGCCA GAA AGCAGGCU GAA AGGAGCAG GAA ACGGGCUU GAA AGCAUACG GAA ACAAGCAU GAA AUCCUCCA GAA AAUCCUCC GAA AAAUCCUC GAA AUCUUGUU GAA ACUUCGAU GAA AUUGGUUU GAA AUCAGGGC GAA ACAGUUUUT GAA ACUUTACAG GAA ACCAGCGU GAA AUGACCAG GAA ACACGUUG GAA ACGCUGAC CUAUGGAUU CCIJACCAG UAUGGATJTC

CUACCAGU

GGAUUCCTJA CCAGUAUG CUACCAGtJA

UGGGACCA

GCAGACAtJU GACAUGCA UGCACAGtJC

UACGCCAA

CACAGUCUA CGCCAACC CCAACCCUC

CCCUGCAC

CACCACAUC CAGUGGUA CCAGUGGUA CUGGCAGC UGGCAGCUA GAAGAAGC AGCCUGCUC

CUACAGAC

CUGCUCCUA CAGACCCG AAGCCCGUA UGCUUGUA CGUAUGCUU

GUAAAGAA

AIJGCUUJGUA

AAGAAUGG

UGGAGGAUU UCCAGGGG GGAGGAUUU

CCAGGGGG

GAGGATJEUC

CAGGGGGG

AACAAGAUC GAAGUCAC AUCGAAGUC ACCAAAAA AAACCAAUA

IJGCCCUGA

GCCCUGAUTU

GAAGGAAA

AAAACUGUA AGTJACGCU CUGUAAGUA

CGCTJGGUC

ACGCUGGtUC AUCCAAGC CUGGUCAUC

CAAGCUGC

CAACGUGUC AGCGTJUGU GUCAGCGUTJ

GUACAAAU

AGCGTJUGUA CAAAUGUG 1859 AUUUGUAC CUGAUGA X 1862 CACAUUrJG CUGAUGA X GAA ACAACGCU 131 1878 1905 1908 1910 1913 1914 1923 1930 1938 1939 1982 1988 2008 2012 2013 2022 2030 2037 2042 2054 2058 2072 2076 20851 2086 2096( 2104 2106 2107C GCUUUGtU

AAGGAGAU

UGGAAGGA

CAUGGAAG

UCACAUGG

AUCACAUG

GGACCCCU

AAUUTUCAG

UGCACAGU

UUGCACAG

ACAACAGG

CAGUGCAC

CUCAAACG

GGLUCUCA

AGGUUCUC

UACCACGU

CAAGCUUG

UGUGAGCC

UUGCCUGU

tJGUGGACC

CCCAUGUGC

3IJGUGAGUC k.CUGGUGUC JtJCUGCAC 3LUUCUUGCC 3AGCAtJCCC

JUUCCAAAC

WGUUUCCAC

:AGIJUIJCC C CUGAUGA X GAA AUGGCTJUC CUGAUGA X GAA ACCCUCUC CUGAUGA X GAA AUGACCCU CUGAUGA X GAA AGAUGACC CUGAUGA X GAA AGGAGAUG CUGAUGA X GAA AAGGAGAU CUGAUGA X GAA AUCACAUG CUGAUGA X GAA ACCCCUGA CUGAUGA X GAA AUUUCAGG CUGAUGA X GAA AAUUUCAG CUGAUGA X GAA ACACACUC CUGAUGA X GAA ACAGGGAC CUGAUGA X GAA AUIJUCUGU CUGAUGA X GAA ACGUAUUU CUGAUGA X GAA AACGUALU CUGAUGA X GAA AGGUTJCUC CUGAUGA X GAA ACCACGUG CUGAUGA X GAA AGCUUGUA UGAUGA X GAA AGCCAAGC ZUGAUGA X GAA AUGUUGCC =UAUGA X GAA ACCGAUGU 'TGAUGA X GAA AUUCGCCC .TUGAUGA X GAA AGUGAUUJC TUGAUGA X GAA ACUGGUGU 'UGAUGA X GAA AACUGGUG 'UGAUGA X GAA AGUEJCUUG 'TJGAUGA X GAA AGCAUCCA 'UJGAUGA X GAA AGAGCAUC UGAUGA X GAA AAGAGCAU GAAGCCAUC

AACAAAGC

GAGAGGGUC AUCUCCUU AGGGUCAUC

UCCULJCCA

GGUCAUCUC

CUUCCAUG

CAUCUCCUU

CCAUGUGA

AUCUCCUUC CAUGUGAU CAUGUGAUC

AGGGGUCC

UCAGGGGUC

CUGAAATJT

CCUGAAAULJ

ACUGUGCA

CUGAAAUUA

CUGUGCAA

GAGUGUGUC

CCUGUUGU

GUCCCIJGUU

GUGCACUG

ACAGAAAUA

CGLJUGAG

AAAUACGUU

UGAGAACC

AAUACGUUU

GAGAACCU

GAGAACCUC

ACGUGGUA

CACGUGGUA

CAAGCUEJG

UACAAGCUU

GGCUCACA

GCUUGGCUC

ACAGGCAA

GGCAACAUC

GGUCCACA

ACAUCGGUC

CACAUGGG

GGGCGAAUC

ACUCACAC

GAAUCACUC

ACACCAGU

ACACCAGUU UGCAAGAA CACCAGUUU

GCAAGAAC

CAAGAACUTJ

GGAUGCUC

UGGAUGCUC

UTJGGAAA

GAUGCUCUU

UGGAAACU

AUGCUCUUU

GGAAACUG

CACCAUGLU LTUUCUAACA 2129 UGULJAGAA CUGAUGA X GAA ACAUGGUG 132 2130 CUGUUAGA CUGAUGA X GAA AACAUGGU 0 2131 2132 2134 2151 2153 2157 2165 2166 2167 2177 2179 2198 2202 2203 2207 2212 2218 2239 2247 2256 22591 2262 2265 2286 2296 2305 2319C 2331 C

GCUGUUAG

UGCUGUUA

UGUGCUGU

ACAAUCAA

CCACAAUC

AAUGCCAC

CAUUCUGA

GCAUUCUG

GGCAUUCU

CCTJGCAGA

GUCCUGCA

AGCAAACA

GCAGAGCA

AGCAGAGC

CLUJGAGCA

CUUAUCUU

GGUCLTIJCU

GACCAGGC

AGCUGUUU

kGGAUGAU

JCUAGGAUC

::GCUCUAGC

kUGCGCUCC .JUUICCGGTJ C kJJIJCUCr-AC

JGUUGUCUC

;,UCUCGCcC ;UCACUUcC CUGAUGA X GAA AAACAUGG CUGAUGA X GAA AAAACAUG CUGAULGA X GAA AGAAAACA CUGAUGA X GAA AUGUCALTU CUGAUGA X GAA AGAUGUCA CUGAUGA X GAA- AUCAAGAU CUGAUGA X GAA AUGCCACA CUGAUGA X GAA AAUGCCAC CUGAUGA X GAA AAAUGCCA CUGAUGA X GAA AGGCAUUC CUGAUGA X GAA AGAGGCAU CUGAUGA X GAA AGUCGCCU CUGAUGA X GAA ACAUAGUC CUGAUGA X GAA AACAUAGU CUGAUGA X GAA AGCAAACA CUGAUGA X GAA AGCAGAGC CUGAUGA X GAA AUCUUGAG MUGAUGA X GAA AUGUCUUU 'UGAUGA X GAA ACCAGGCA 'TUGAUGA X GAA AGCUGULTJ 'TGAUGA X GAA AUGAGCUG UTGAUGA X GAA AUGAUGAG .UGAUGA X GAA AGGAUGAU UGAUGA X GAA AUCAUGGO 7UGAUGA X GAA AUUUCCGG 'TUGAUGA X GAA AUUJCUCCA tIGAUGA X GAA AUGGUUGU 'JGATJGA X GAA AUGGUCTJC ACCAUGUUU

UCUAACAG

CCAUGUULTIJ

CUAACAGC

CAUGUUtUtC UAACAGCA UGUUUUCUA

ACAGCACA

AAUGACAUC

UUGAUUGU

UGACAUCUU

GAUUGUGG

AUCUTUGAUU

GUGGCAUUT

UGUGGCAUU UCAGAAUG GUGGCAUUtJ CAGAAUGC UGGCAUUtJC AGAAUGCC GAAUGCCUC UCUGCAGG AUGCCUCUC

UGCAGGAC

AGGCGACUA UGUUUGCU GACUAUGUU

UGCIJCUGC

ACUAUGIJUU GCUCUGCU UGUUUGCUC

UGCUCAAG

GCUCUGCUC

AAGAUAAG

CUCAAGAUA

AGAAGACC

AAAGACAUU

GCCUGGUC

UGCCUGGUC

AAACAGCU

AAACAGCUC AUCAUCCU CAGCUCAUC

AUCCIJAGA

CUCAUCAUC

CUAGAGCG

AUCAUCCUA GAGCGCAU CCCAUGAUC ACCGGAAA CCGGAAAUC UGGAGAAU UGGAGAAUC

AGACAACA

ACAACCAUU

GGCGAGAC

GAGACCAUUJ

GAAGUGAC

AAGUGACUU GCCCAGCA 2341 UGCUGGGC CUGAUGA X GAA AGUCAC1U 133 2351 2359 2362 2373 2374 2381 2382 2403 2410 2411 2418 2421 2449 2451 2481 2483 25.05 2508 2532 2534 25351 2538 2541 2567 2574 2577 *2 2578C 2580 C 2583 C

GAACCAUG

UGUCIJUUG

UUGUCUU

GAAUCUUC

AAUGCCUG

CAAUGCCU

CUCAGUAC

UCUCUCAG

CCUGCGGA

ACCCUGCG

CAGGUGUA

GGCAGGUG

CAGCCAAG

GCACAGCC

AUUAUGAA

CUAUUAUG

JCUAUUAU

CCUUCUAU

3CACCUUC

JGACUUCC

kGGAUAAU

~CGAGGAU

;ACGAGGA

~CGACGAG

;UGCCGAC 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 -UGAUGA X =TJAUGA xC :UGAUGA XC UGAUGA XC .UGAUGA XC UGAUGA X GAUUUCCA CUGAUGA X UGGGGUAG CUGAUGA X GUGUGGGG CUGAUGA X AACCAUGU CUGAUGA X GAA AUG CUGGG GAA AUUIJCCAG GAA AGGAUUUC GAA AUGUGUGG GAA AAUGUGUG GAA ACCAUGUA GAA AACCAUGU GAA ACCAGGGU GAA AUCUUCUA GAA AAUCUUCU GAA AUG CCUGA GAA ACAAUGCC GAA AGUCAGGU GAA AUAGUCAG GAA AGGCCUCC' GAA AGAGGCCU GAA ACAUUGCA GAA AGGACAULJ GAA AGCGUCUC GAA AGAGCGUC GAA AAGAGCGU 3AA AUGAAGAG 7AA AUUAUGAA 7AA AGUUGGUC 3AA ACUUCCAA 'AA AUGACUUC ,AA AAUGACUU ,AA AUAAUGAC ;AA AGGAUAAU CCCAGCAUC

UGGAAAUC

CUGGAAAUC

CUACCCCA

GAAAUCCUA

CCCCACAC

CCACACAUrJ

ACAUGGUU

CACACAUUA

CAUGGUUC

UACAUGGUU

CAAAGACA

ACAUGGUTJC

AAAGACAA

ACCCUGGUA

GAAGAUUC

UAGAAGAUU

CAGGCALU

AGAAGAUUC

AGGCAUUG

UCAGGCAUU

GUACUGAG

GGCAUtJGUA

CUGAGAGA

ACCUGACUA

UCCGCAGG

CUGACUAUC

CGCAGGGU

GGAGGCCUC

UACACCUG

AGGCCUCUA

CACCUGCC

UGCAAUGUC

CUTUGGCUG

AAUGUCCUU

GGCUGUGC

GAGACGCUC

UUCAUAAU

GACGCUCUU

CAUAAUAG

ACGCUCUUC

AUAAUAGA

CUCUUCAUA

AUAGAAGG

UUCAUAAUA

GAAGGUGC

GACCAACUU

GGAAGUCA

UUGGAAGUC

AUUAUCCU

GAAGUCAUIJ

AUCCUCGU

AAGUCAUUA

UCCUCGUC

GUCAUUAUC

CUCGUCGG

AUTJAUCCUC

GUCGGCAC

AUCCUCGUC

GGCACUGC

2586 GCAGUGCC CUGAUGA X GAA ACGAGGAU 134 2601 AACAUGGC CUGAUGA X GAA AUCACUGC GCAGUGAUU GCCAUGUtJ 2609 2610 26'12 2613 2619 2622 2623 2625 2628 2631 2634 2637 2646 2647 2681 2684 2687 2689 26911 2694 2701 2711C 2717 C 2738C 2743 C 2744 2765 C 2766 U) 2787 G

GCCAGAAG

AGCCAGAA

GGAGCCAG'

AGGAGCCA

ACAAGAAG

AUGACAAG

AAUGACAA

ACAAUGAC

AGGACAAU

CGUAGGAC

GUCCGUAG

ACGGUCCG

GCCCGCUEJ

GGCCCGCU

UAGACAAG

CAAUAGAC

IJGACAAUA

CAUGACAA.

JCCALTGAC

3GAUCCAUC

JUCAUCUGC

:CAAGGGcC ;CtCAUC :AUAAGGC

C

;GCAUCAU

C

rGGCAUCA

C

CCUGGGG

C

rCCCUJGC GtJUJCC C CUGAUGA X GAA ACAUGGCA CUGAUGA X GAA AACAUGGC CUGAIJGA X GAA AGAACAUG CUGAIJGA 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 AGCCUGtJC CUGAUGA X GAA AGUAGCCU CUGAUGA X GAA ACAAGUAG :UGAUGA X GAA AGACAAGU UGAUGA X GAA AUAGACAA 'UGAUGA X GAA ACAAUAGA ~UGAUGA X GAA AUCCAUGA UTGAUGA X GAA AUUCAUCU UTGAUGA X GAA AGGGCAAU :UGAUGA X GAA AGCGUIJCA UGAUGA X GAA AGGCAAGC UGAUGA X GAA AAGGCAAG UJGAUGA X GAA AUUCCCAC IJGAUGA X GAA AAUUCCCA UGAUGA X GAA AGUUUCAG UGCCAUGUIJ

CUUCUGGC.

GCCAUGUUC

UUCUGGCU

CAUGUUtCUU

CUGGCUCC

AUGUtJCUUC

UGGCUCCU

UTJCUGGCUC

CUJICUUGU

UGGCUCCUU

CUJUGUCAU

GGCUCCUUC

UUGUCAUTJ

CUCCUUCU

GUCAUUGU

CULJCUUGUC

AUUGUCCU

CUtJGUCAUU

GUCCUACG

GUCAUUGUC

CUACGGAC

AUUGUCCUA

CGGACCGU

CGGACCGUU

AAGCGGGC

GGACCGUUA

AGCGGGCC

GACAGGCUA

CUUGUCUA

AGGCUACUU

GUCUAUUG

CUACUTUGUC

UAUTUGUCA

ACUUGUCUA

UUGUCAUG

UtJGUCUAULJ

GUCAUGGA

UCUALTJGUC

AUGGAUCC

UCAUGGAUC

CAGAUGAA

AGAUGAAUU

GCCCUUGG

AUTUGCCCJU

GGAUGAGC

UGAACGCJI

GCCUIJAUG

GCUtJGCCUU

AUGAUGCC

CUEJGCCUUA

UGAUGCCA

GUGGGAAUU

CCCCAGGG

UGGGAAUJC

CCCAGGGA

CUGAAACUA

GGAAAACC

135 2797 GCGGCCAA CUGAUGA X GAA AGGUUUUC 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( 3015 3024

CCGCGGCC

CUUGGCCG

ACUtJGGCC

UCTJGCCUC

AAUUCCAA

CAAUUCCA

UCAATICC

GUCLTTJGUC

UGUUUUGC

UUTGACGGC

AACAUCUU

CUUCTUtC

GAGGGCUC

UCAGACAU

UGAGUTUCA

AGGAUCUU

UGGAUGAG

AUGUGGAU

CCAAUGUG

LJGGUGACC

GAGAUGGU

CACATJGA

kCCACAUU 3CGCCUAG

AGGCGCCC

7ACCAUGAC

WCACCAUC

AUUCCAC C CUGAUGA X GAA AGAGGULUJ CUGAUGA X GAA AGGCACCG CUGAUGA X GAA AAGGCACC CUGAUGA X GAA AUCACUTJG CUGAUGA X GAA AGCGUCUG CUGAUGA X GAA AAGCGUCU CUGAUGA X GAA AAAGCGUC CUGAUGA X GAA AUUCCAAA CUGAUGA X GAA AGUCGCUG CUGAUGA X GAA ACUGUUUUn CUGAUGA X GAA ACGGCUAC CUGAUGA X GAA ACATJCUUJG CUGAUGA X GAA AUGCUCGC CUGAUGA X GAA AGGGCUCG CUGAUGA X GAA ACAUGAGG CUGAUGA X GAA AGULJCAGA CUGAUGA X GAA AUCUUGAG CUGAUGA X GAA AGGAUCUIJ CUGAUGA X GAA AUGAGGAU CUGAUGA X GAA AUGUGGAU CUGAUGA X GAA ACCAAUGU -UGAUGA X GAA AUGGUGAC 'UGAUGA X GAA AGAUGGTJG :UGAUGA X GAA AGGIJUCAC 7UGAUGA X GAA AGGAGGUUJ UTGAUGA X GAA AGGCCCUC :UGAUGA X GAA AGAGGCCC :LGAUGA X GAA AUCACCAU GAAAACCUC UUtGGCCGC AAACCUCUU

GGCCGCGG

CGGUGCCUU

CGGCCAAG

GGUGCCUUC

GGCCAAGU

CAAGUGAUtJ

GAGGCAGA

CAGACGCUU

UUGGAAUU

AGACGCtJUU UGGAAuUG GACGCLJUUU GGAAIJUGA ULtJGGAAUU GACAAGAC CAGCGACUU GCAAAACA AAAACAGUA GCCGUCAA GUAGCCGUC AAGAUGUU CAAGAUGUU GAAAGAAG GCGAGCAUC GAGCCCUC CGAGCCCUC AUGUCUGA CCUCAUGUC UGAACUCA UCUGAACUC AAGAUCCU CUCAAGAUC

CUCAUCCA

AAGAUCCUC

AUCCACAU

AUCCUCAUC CACAUtJGG AUCCACAJU GGUCACCA ACAUUGGUC

ACCAUCUC

GUCACCAUC UCAAtJGUG CACCAUCUC AAUGUGGU GUGAACCUC

CUAGGCGC

AACCUCCUA GGCGCCUG GAGGGCCUC UCAUGGUG GGGCCUCUC

AUGGUGAU

AUGGUGAUTU

GUGGAAUUL

UGUGGAAUU CUGCAAGU 3032 ACUUGCAG CUGAUGA X GAA AUUtCCACA 136 3033 AACUEJGCA CUGAUGA X GAA AAUUCCAC GUGGAAUUC UGCAAGUUi 3041 3042 3051 3053 3058 3059 3062 3063 3083 3084 3087 3088 3092 3094 3113 3114 3131 3135 20 3144 3146C 3154 t 3167 3177C 3194 A 3203C 3209 C 3210 U 3213 U

GGUUTJCCA

AGGIJUUCC

UAAGUUGA

AGUAAGUEJ

CCGUAAGU

CCCGUAAG

UGCCCCGU

UUGCCCCG

AGGGAACA

UAGGGAAC

UtJAUAGGG

CUUAUAGG

tJGCJCUtJA

UEJUGCUCU

CCUGGCGG

CCCUGGCGC

CCCCAACGC

%GCUCCCC

C

JCCACGGA

C

;AUCCACGC

JCUUUUCAC

JGCUGUCC

C

'TUGCUGGU

C

~GCUGGCA

C

AAAGCCU

C

'CUCAACA

C

CCtJCAAC

C

UCUCCUC

C

CUGAUGA X GAA ACUUGCAG CUGAUGA X GAA AACUUGCA CUGAUGA X GAA AGGUUUCC CUGAUGA X GAA AUAGGUUU CUGAUGA X GAP. AGUUGAUA CUGAUGA X GAP. AAGUUGAU CUGAUGA X GAP. AGUAAGLU CUGAUGA X GAlA AP.GUAAGU CUGAUGA X GAP. AUTJCAUUU CUGAUGA X GAP. AAUUCAU1J CUGAUGA X GAP. ACAPAtJEJC CUGAUGA X GAP. AACAAAtU CUGAUGA X GAP. AGGGAACA UGAUGA X GAP. AUAGGGAA 7UGAUGA X GAP. AGCGUGCC 'UJGAUGA X GAP. AAGCGUGC UGAUGA X GAP. AGUCCUUG UGAUGA X GAP. ACGUAGUC UGAUGA X GAP. AGCUCCCC .UGP.UGA X GAlA AGAGCUCC UJGAUGA X GAP. AUCCACGG UGAUGA X GAA AGCGUCUU UGAUGA X GAP. AUGCUGUC UGAUGA X GAP. AGCUCUGG UGAUGA X GAP. AGCUGGCA JGAUGA X GAP. AGCCUGAG LGAtJGA X GAP. AP.GCCUGA UGAUGP. X GAP. ACAAAGCC CUGCAAGUU

UGGAAACC

UGCAP.GUUU

GGAAACCU

GGAAACCUA

UCAACUTUA

AAACCUAUC

AACUUACIJ

UP.UCAACIJU

ACTLJACGG

AUCAP.CUUA

CUULACGGG

AP.CUUACUUI

ACGGGGCA

ACULJACUUA

CGGGGCAA

AAAUGAAUU

UGUUCCCU

AP.UGAP.UUU

GUEJCCCUA

GAAIJUUGUU

CCCUAUAA

AAtUETJGUUC

CCUALTAAG

UGTJUCCCUA

UAP.GAGCA

UTUCCCUAUA

AGAGCAAA

GGCACGCUU

CCGCCAGG

GCP.CGCUUC

CGCCP.GGG

CAAGGACUA

CGUUGGGG

GACUACGUU

GGGGAGCU

GGGGAGCUC

UCCGUGGA

GGAGCUCUC

CGUGGAUC

CCGUGGAUC

UGAAAAGA

AAGACGCUU

GGACAGCA

GACAGCAUC

ACCAGCAG

CCAGAGCUC

UGCCAGCU

UGCCP.GCUC

AGGCUUUG

CUCAGGCUTJ

UGUEJGAGG

tJCPGGCUUTJ

GUUGAGGA

GGCUUUGUTJ GAGGAGAP.

3224 CACUGAGC CUGAUGA X GAP. AUUIJCUCC GGAGAAP.UC GCUC-AGuG 137 3228 ACAUCACU CUGAUGA X GAA AGCGAUUU 9 *99.

9.

9*9* 9 9 323' 325: 325, 326( 327E 327( 3284 3292 10 3294 3297 3301 3302 3308 3309 3319 3332 333.3 3335 20 3341 3352 3354 3381 3382 3384 3387 3389 3405 3406 3411 7 UCUUCCUC 3 UIJCTTCAG I GIJUCUUCA 5AGUCCUUG

AGGUCAGG

AAGGUCAG

GAUGCUCC

ACAGAUGA

UAACAGAU

CUGUAACA

GAAGCUGU

GGAAGCUG

CCACUUGG

GCCACLTUG

CAUGCCCU

AUG CCAAG

GAUGCCAA

UUIGAUGCC

ACUIJCCLU

CCUGUGGAC

UCCCUGUGC

GAUAGGAGC

CGAUAGGA

C

UCCGAUAGC

TJUCUCCGAC

ucurjcucc

CAGAUCTUC

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA CUGAUGA CtJGAUGA CUGAUGA CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA x ZUGAUGA X -UGAUGA X 7UGAUGA X 7UGAUGA X UGAUGA X ~UGAUGA X 'TUGAUGA X .JGAUGA X 'IUGAUGA X TUGAUGA X X GAA ACAUCACU X GAA AGCUUCUU X GAA AAGCUtJCU X GAA ACAGUUCU K GAA AGUCCUUG ,K GAA AAGUCCUUJ CGAA AGGUCAGG CGAA AUGCUCCA SGAA AGAUCCUC GAA AUGAGAUG GAA ACAGAUGA GAA AACAGAUG GAA AGCUGUAA GAA AAGCUGUA GAA AGCCACUUJ GAA ACUCCAUG GAA AACUCCAU GAA AGAACUCC GAA AUG CCAAG GAA ACACUtJCC GAA AUACACUU GAA AUGUUUCG GAA AAUGUUTJC GAA AGAAUGU GAA AGGAGAAU GAA AUAGGAGA GAA ACCACAU GAA AACCACAU GAA AUCUUJAAC AAAUCGCUC

AGUGAUGU

AGUGAUGUA

GAGGAAGA

AAGAAGCUtJ

CTJGAAGAA

AGAAGCTEC UGAAGAAc AGAACUGUA CAAGGAcu CAAGGACTJU

CCUGACCU

AAGGACUUC CUGACCUUr CCUGACCUU

GGAGCAUC

UGGAGCAUC

UCAUCUGU

GAGCAUCUC

AUCUGUIJA

CAUCUCAUC

UGUACAG

UCAUCUGUU

ACAGCULJC

CAUCUGUUA

CAGCUUCC

UtJACAGCUU

CCAAGUGG

UACAGCUUC

CAAGUGGC

AAGUGGCUA

AGGGCAUG

CAUGGAGUUI

CUUGGCAU

AUGGAGtJUC

UUIGGCAUC

GGAGUEJCUU

GGCAUCAA

CUUGGCAUC

AAGGAAGU

GGAAGUGUA

UCCACAGG

AAGUGUAUC

CACAGGGA

CGAAACAUU

CUCCUAUC

GAAACAUUC

UCCUAUCG

AACAUUCUC

CIJAUCGGA

AUUCUCCUA

UCGGAGAA

UCUCCUAUC

GGAGAAGA

AAUGUGGUTU

AAGAUCUG

AUGUGGUUA

AGAUCUGU

GUUAAGAUC UGUGACUTJ ACAGAUCU CUGAUGA x AAGUCACA CUGAUGA X 138 3419 CCAAGCCG CUGAUGA X GAA AGUCACAG 0e 06 4 0*6 4 0 4 3420 3425 3438 3439 3440 3442 3454 3455 3459 3480 3484 3485 3510 3511 3512 3513 3522 3524 3531 35322 3548C 3550C 3551 3552 3560 C 3564 3573A 3575C

GCCAAGCC

CCCGGGCC

UCtUTJAUA

GUCTJTJAU

GGUCUUJA

CGGGUJCUU

UCUGACAU

UITJCUGACA

CCUUUuJCU

LUCAAAGG

CCACLITJCA

UCCACTUC

CUGUCAAA

UCUGUCAA

CUCtJGUCA tCUCUGUC

~UUGUGUA

3AAUTUGUGC

JCGCUCUGC

k.UCGCUCUC

ZACCGAAAC

:ACACCGAC

LCACACCGC

LACACACC

C

CCAGAGC

C

.UUUTCCCA

C

AGGAAAA

UAAGGAA Ci

CUGAUGA

CUGAUGA

CtJGAUGA

CUGAUGA

CUGAIJGA

CUGAUGA

CLIGAUGA

CUGAUGA

CUGAUGA

CIJGAUGA

CUGAUGA

CUGAUGA

CtJGAUGA

CUGAUGA:

CUGAIJGA

7UGAUGA

UJGAUGA

rnGAUGA)

UTGAUGA)

UTGAUGA Y 'TUGAUGA x 'UJGAUGA X UGAUGA X UGAUGA X UGAUGA X UGAUGA X (JGAUGA X LIGAUGA X 4 x x

K

C

X GAA AAGUCACA GAA AGCCGAAG GAA AUGUCCCG GAA AAUGUCCC X GAA AAAUGUCC X GAA -AUAAAtJGU K GAA AUCCGGGU GAA AAUCCGGG GAA ACAUAAUC CGAA AGUC .GG~C GAA AGGGAGUC GAA AAGGGAGU GAA AUGGUUEJC GAA AAUGGUUUL GAA AAAUGGUU GAA AAAAUGGU GAA ACTJCUGUC GAA AUACUCUG GAA AIJUGUGUA GAA AAU7UGUGU GAA ACCACACA GAA AGACCACA GAA AAGACCAC GAA AAAGACCA GAA ACACACCG GAA AGCAACAC GAA AUUUCCCA GAA AUAUUUCC CUGIJGACLJ

CGGCUUGG

UGUGACUUC

GGCUUGGC

CUUCGGCUU

GGCCCGGG

CGGGACAUU

UAUAAAGA

GGGACAUUU

AUAAAGAC

GGACAUUUA

UAAAGACC

ACAIUUAtJA

AAGACCCG

ACCCGGAUU

AUGUCAGA

CCCGGAUUA

UGUCAGAA

GAUUAUGUC

AGAAAAGG

GCCCGACUC

CCUUUGAA

GACUCCCUtJ

UGAAGUGG

ACUCCCUUU

GAAGUGGA

GAAACCAUU UUJtGACAG AAACCAUUU

LUGACAGA

AACCAUUUU

UGACAGAG

ACCAtUUUUU

GACAGAGU

GACAGAGUA

UACACAAU

CAGAGUAUA CACAAtUC IJACACAAUU

CAGAGCGA

ACACAAUUC

AGAGCGAU

UGUGUGGtJC

UIJUCGGUG

UGUGGtJCUU UCGGtJGUG GUGGUCTJUU

CGGUGUGU

UGGUCUUUC

GGUGUGUU

CGGUGUGUU

GCUCUGGG

GUGUUGCUC

UGGGAAAU

UGGGAAAUA

UUEJUCCUU

GGAAAUAtJU UTJCCUTUAG 3576 CCUAAGGA CUGAUGA X GAA AAUAUUUC GAAAUAUUU UCCUUAGG 139 3577 ACCUAAGG CUGAUGA 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 37584 37684 38034 3805

CACCUAAG

AGGCACCU

GAGGCACC

GGUAUGGG

CCCCAGGG

UCAAUCUU

UCUUCAUC

UCCUACAA

CUCCUACA

UCUCCUAC

CAAUCUCC

CUUCULUC

CCGCALUC

GUAGUCAG

GGGUAGUG

UUCUGGGG

UGGUCUGG

CUGAAAAC

ACUCUGAA

AACUCUGA

CAACUCUG

CCAACUCU

GCUCCACC

GUUUCCCA

GGUUUCCC

GCUTUGCAG

GAACAAUA

kIAGAACAAC 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 7UGAUGA X 7UGAUGA X 'UGAUGA X 'UGAUGA X UTGAUGA X UTGAUGA X GAA AAAAUAUU GAA AGGAAAAU GAA AAGGAAAA GAA AGGCACCU GAA AUGGGGAG GAA ACCCCAGG GAA AUCUUGAC GAA AUUCUUCA GAA AAUTUCLUC GAA AAAUUCUU GAA ACAAAALU GAA AUCUCCUA GAA AGUTUCCUU GAA AGCCCGCA GAA AGUCAGGA GAA AGUGUAGU GAA ACAUUJUCU GAA AGGGUCUC GAA ACGAGGGU GAA AACGAGGG GAA AAACGAGG GAA AAAACGAG GAA ACUCUGAA GAA AUGCUCCA GAA AAUGCUCC GAA AGGUUUCC GAA AGUCUUUG 3AA AUAGUCUU AAAUAUUUU CCUUAGGU AAUAUUUUC CUUAGGUG AUUUUCCUU

AGGUGCCU

UUUUCCUUA GGTJGCCUC AGGUGCCUC CCCAUACC CUCCCCAUA CCCUGGGG CCUGGGGUC AAGATTGA GUCAAGAJU GAUGAAGA UGAAGAAUU UUGUAGGA GAAGAAUUU UGUAGGAG AAGAAUUUEJ GUAGGAGA AAUUJGUA GGAGAUUG UAGGAGAUU GAAAGAAG AAGGAACUA GAAUGCGG UGCGGGCUC CUGACUAC UCCUGACUA CACUACCC ACUACACUA CCCCAGAA AGAAAUGUA CCAGACCA GAGACCCUC GUUUUCAG ACCCUCGUU UUTCAGAGU CCCUCGUUEJ UCAGAGUU CCUCGUUUU CAGAGUUG CUCGUUUUC AGAGUUGG UUCAGAGUIJ GGUGGAGC UGGAGCAUU UGGGAAAC GGAGCAUtJU GGGAAACC GGAAACCUC CUGCAAGC CAAAGACUA

UAUUGUTUC

AAGACUAUA UUGUUCUU GACUAUAUU GUUCUUCC 3807 GGAAGAAC CUGAUGA X GAA AUAUAGUC 140 3810 AUUtGGAAG CUGAUGA X GAA ACAAUAUA UAUAUJUGUU CUuICCAAU

S

S

*.SSS.

S

3811 3813 3814 3821 3847 3848 3855 3857 3865 3869 3876 3877 387,8 3883 3914 3915 3919 3920 3939 3943 3946 39471 3949( 3951C 3961C 3987 3995 3996

CAUUGGAA

GACALUGG

UGACALUG

GUGUCIJCU

GAGUCCAG

AGAGUCCA

GGCAGGGA

UAGGCAGG

AGGUGAGG

AAACAGGU

AUACAGGA

CAUACAGG

CCAUACAG

UIJCCJCCA

CAUAALTGG

UCAUAAUG

GUUGUCAU

rJGUIJGUCA

LJAAUGACU

GAGAUAAU

CUJGGAGAU

JCUGGAGAC

3UUCIJGGAC UGUUCUG C .'UtJCGCU C LAUGUUYE C JAUCUUCA C LUAUCUUTC C CTJGAUGA X GAA AAcAAuAu CUGAUGA X GAA AGAACAAU CUGAUGA X GAA AAGAACAA CUGAUGA X GAA ACAUUGGA CUGAUGA X GAA AUCCUCU 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 ACAGGAAA CUGAUGA X GAA AUUUGGGG CUGAUGA X GAA AALTUUGGG CUGAUGA X GAA AUGGAALTU CUGAUGA X GAA AAUGGAAU -UGAUGA X GAA AUUCCUGC 'UGAUGA X GAA ACUGAUUC 'TUGAUGA X GAA AUGACUGA 'TUGAUGA X GAA AAUGACUG UGAUGA X GAA AUAAUGAC ~UGAUGA X GAA AGAUAAUG UGAUGA X GAA ACUGUUCU UGAUGA X GAA ACACUCAC UGAUGA X GAA AUGLUUUU 'UGAUGA X GAA AAUGUUUU

AUAUUGUU

AUULGUUICU

UTUGUUCUU

UCCAAUGU(

AAGAGGALTI

AGAGGAUJC

UCUGGACUC

UGGACUCUC

CCCUGCCUI

GCCUACCUC

UCACCUGUL:

CACCUGUU

ACCUGLUUC

UUUCCUGUA

CCC CAAAUTJ

CCCAAAUUC

AAIJUCCAUU

AUUTCCAUUTA

GCAGGAAUC

GAAUCAGUC

UCAGUCAUU

CAGUCAUUtA

GUCALTJAUC

CAUJTAUCUC

AGAACAGUA

GUGAGUGUA

AAAAACAUU

AAAACAUUU

C UUCCAAUG U CCAAUGUC :7 CAAUGUCA

AGAGACAC

J CUGGACUC

UGGACUCU

UCCCUGCC

CCUGCCUA

CCUCACCU

ACCUGUUtJ

UCCUGUAU

rCCUGUAUG

CUGUAUGG

UGGAGGAA

CCAIJTJAUG

CAUUAUGA

AUGACAAC

UGACAACA

AGUCAUTUA

AUUAtTCUC

AUCUCCAG

UCUCCAGA

UCCAGAAC

CAGAACAG

AGCGAAAG

AAAACALUU

UGAAGAUA

GAAGAUAU

4003 CAAUGGGA CUGAUGA X GAA AUCUUCAA UUGAAGAUA

UCCCALTUG

141 4005 UCCAAUGG CUGAUGA X GAA AIJAUCUUC 44 4010 4026 4035 4068 4071 4076 4093 4112 4113 4115 4117 4121 4123 15 4124 4125 4144 4157 4166 4175 4193 4199 4205 4207 4211 4235 4238 4257 4258

GIJUCCUCC

AUCACUUtJ

UCAUCUGG

GAUGCAAG

UCUGAUGC

GCUCUTUCU

GUCUUCCA

AUGGAGAU

GAUGGAGA

AAGAUGGA

AAAAGAUG

CACCAAAA

UCCACCAA

UUCCACCA

AUUCCACC

CCUGCUU

AGGCCACA

AGCCtTUCC

UCUGGUUG

CAGACUGG

GAUACCCA

CUGAGUGA

AJJCUGAGUC

LJGUCAUCU

CGCUGGAGC

CGUCGCUG C kUCUUUAA C

!AUCUUUAC

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 IUGAUGA X UTGAUGA X UGAUGA X UGAUGA X UTGAUGA X UGAUGA X UGAUGA XC .TUGAUGA XC GAA AUGGGAUA GAA ACUUCTJGG GAA AUCACUUUI GAA ACCAUCCC GAA AGGACCAU GAA AUG CAAGG GAA AGUUUTJCA GAA AUUtJGUUC GAA AAUUUGTU GAA AUAAUUTUG GAA AGAUAAUU GAA AUGGAGAU GAA AGAUGGAG GAA AAGAUGGA GAA AAAGAUGG GAA ACUGGGCA GAA ACUCCCUG GAA AGGCCACA GAA AGCCUUCC GAA AGCCACUG GAA ACUGGUAG GAA ACCCAGAC .7AA AUACCCAG 3AA AGUGAUAC 37AA ACACGGUG MAA AGUACACG ,AA AGUCCUGC ;AA AAGUCCUG GAAGAUAUC

CCAUUGGA

UAUCCCAUU GGAGGAAC CCAGAAGUA

AAAGUGAU

AAAGUGAUC

CCAGAUGA

GGGAUGGUC

CUIJGCAUC

AUGGUCCLIU

GCAUCAGA

CCUUGCAUC

AGAAGAGC

UGAAAACUC

UGGAAGAC

GAACAAALTU

AUCUCCAU

AACAAAUUA

UCTJCCAUC

CAAAUUAUC

UCCAUCUU

AAUUAUCUC CAUCUUUtJ AUCUCCAUC

UUUTUGGUG

CUCCAUCUTLJ UUGGUGGA UCCAUCLUU

UGGUGGAA

CCAUCUUUUJ GGUGGAAU UGCCCAGUA AAAGCAGG CAGGGAGUC

UGUGGCCU

UGUGGCCUC GGAAGGCU GGAAGGCUC

CAACCAGA

CAGUGGCUA

CCAGUCUG

CUACCAGUC UGGGUAUC GUCUGGGUA

UCACUCAG

CUGGGUAUC

ACUCAGAU

GUAUCACUC

AGAUGACA

CACCGUGUA

CUCCAGCG

CGUGUACUC

CAGCGACG

GCAGGACUU UUAAAGAU CAGGACUUU

UAAAGAUG

AGGACUUrJU AAAGAUGG 4259 CCAUCUUU CUGAUGA X GAA AAAGUCCU 142 4260 ACCAUCUU CUGAUGA X GAA AAAAGUCC e 4281 4282 4292 4311 4316 4321 4322 4323 10 4336 4341 4348 4360 4369 15 4387 4388 4392 4393 4394 4395 4402 4405 4406 4408 4409 4410 4425 4433( 4434

UCAGCGUG

GUCAGCGU

UGGUCCCU

CAGGAGGU

UIJAAACAG

UCCAUUUA

UUCCATU

CUTUCCAUU

CGGGACAG

GGAGCCGG

UGGGGGCG

AUTUUCCAG

UCUCUCGU

GAAAAUCU

UGAAAAUC

CACUTJGAA

ACACUTJGA

AACACUUG

CAACACUU

GAAAGAAC

GUGGAAAG

GGUGGAAA

GUGGUGGA

"GUGGUGG

3GGUGGUG kAUGUGGCC iAAAAUCAC JGAAAAtJC

C

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 CUGAUJGA X GAA AGCCGGGA CUGAUGA X GAA AGUUGGGG CUGAUGA X GAA ALUUCCAG CUGAUGA X GAA AGCAGCAC CUGAUGA X GAA AAGCAGCA CUGAUGA X GAA AUCUAAGC CUGAUGA X GAA AAUCUAAG CUGAUGA X GAA AAAUCUAA CUGAUGA X GAA AAAAUCUA CUGAUGA X GAA ACACUUGA UGAUGA X GAA ACAACACU -UGAUGA X GAA AACAACAC UGAUGA X GAA AGAACAAC UJGAUGA X GAA AAGAACAA :UGAUGA X GAA AAAGAACA UJGAUGA X GAA ACUUCCGG UTGAUGA X GAA AUGUGGCU UGAUGA X GAA AAUGUGGC GGACUUUUA

AAGAUGGU

GCUGCAGUIJ

CACGCUGA

CUGCAGUtJC

ACGCUGAC

CGCUGACUC

AGGGACCA

CUGCAGCUC

ACCUCCUG

GCUCACCUC

CUGUTEAA

CCUCCUGUU UAAAUGGA CUCCUGUUU

AAAUGGAA

UCCUGUTUUA

AAUGGAAG

GAAGUGGUC

CUGUCCCG

GGUCCUGUC

CCGGCUCC

UCCCGGCUC

CGCCCCCA

CCCCAACUC

CUGGAAAU

CUGGAAAUC

ACGAGAGA

GUGCUGCUTU

AGAULJUC

UGCUGCUUA

GAUUTUUCA

GCUUAGAUU

LUCAAGUG

CULJAGAUUU

UCAAGUGU

UUAGAUUUEJ

CAAGUGU

UAGAUUUtJC

AAGUGUUG

UCAAGUGtjU GUUCUUUtC AGUGIJUGUJI CUUtJCCAC GUGUUGUUC

UUUCCACC

GUUGUEJCUU

UCCACCAC

UUGUUCUUIJ CCACCACC UGUUCUUUC

CACCACCC

CCGGAAGUA

GCCACAUU

AGCCACAUU UGAULTUtUC GCCACAUUU

GALUUJUCA

CAUUUGAUU UUCAUUUU 4438 AAAAUGAA CUGAUGA X GAA AUCAAAUG 143

C

a. a

C

a 4439 4440 4441 4444 4445 4446 4447 4461 4477 4480 4483 4491 4492 4493 15 4525 4530 4532 4535 4537 4539 4540 4541 4542 4546 45471 4550 4551 4552 4558 4561

AAAAAUGA

CAAAAAUG

CCAAAAAU

CCUCCAAA

UCCUCCAA

CUCCUCCA

cCUccucc

UGCAGUCU

CUGAGGAC

GCCCUGAG

AAUGCCCU

UCUCUGGA

UTJCUCUGG

CUUCUCUG

GUAGAGUC

AGAGAGUA

AAAGAGAG

GGAAAAGA

AUGGAAAA

GAAUGGAA

LJGAAUGGA

AXJGAAUGG

A.AUGAAUG

LUUAAAUG

LJUUUAAAU

GACUUULJA

3GACUUUU kGGACUUtJ

JTJAUAUAG

kICALTUAUA CUGAUGA X CUGAUGA X CUGAUGA X CUGAUJGA 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 CtJGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X4 -UGAUGA X 2UGAUGA X UTGAUGA X :UGAUGA X GAA AAUCAAAU GAA AAAUCAAA GAA AAAAUCAA GAA AUGAAAAU GAA AAUGAAAA GAA AAAUGAAA GAA AAAAUGAA GAA AGGUCCCU GAA AGCUCCUU GAA ACAAGCUC GAA AGGACAAG GAA AUGCCCUG GAA AAUGCCCU GAA AAAUGCCC GAA ACACATJEC 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 ACUUUrJAA 3AA AGGACUU AUUUGAUUU

UCAUTUUU

UEJUGAUUUu C-AUUUUUG UUGAUUUUC

AUUUUUGG

AUUUtJCAIJU

UUUGGAGG

UUUUCAUEJU

UUGGAGGA

UUEJCAUUEJU

UGGAGGAG

UUtCAUUUEJU GGAGGAGG AGGGACCUC

AGACUGCA

AAGGAGCUU GUCCUCAG GAGCUUGUC CUCAGGGC CIJUGUCCUC AGGGCAU CAGGGCAUU UCCAGAGA AGGGCAUUU CCAGAGAA GGGCAUUULC CAGAGAAG GAAUGUGUU GACUCUAC UGUUGACTJC UACUCUCU UUGACUCUA CUCUCtUUU ACUCtJACUC UCUUUUICC UCUACIJCUC UUUCCAU UACUCUCUU UUCCAUtJC ACUCUCUTJ UCCAUUJCA CUCUCUUIJU CCAUUCAU UCUCUUtJUC CAUUICAUU UUULUCCAUU CAUUUJAAA UUTJCCALUJC ALUUAAAA CCAUUTCAUU UAAAAGUC CAUUCALUJU AAAAGUCC AUTJCAUUUA AAAGUCCU UUAAAAGUC

CUAUAUAA

AAAGUCCUA UAUAAUGU 144 4563 GCACAUJA CUGAUGA X GAA AUAGGACU AGUCCUAUA UAAUGUGC 4565 GGGCACAI

C

4583 4585 4589 4595 4596 4609 4610 4611 4625 4629 4632 4654 15 4668 4683 4684 4691 4709 4722 4726 4728 4732 4740 4741 47581 4771 4772 4811(

GGUAGUGA

CUGGUAGU

UUAACUGG

UULUGCUUU

UULUUGCUU

GUGUUUGA

CGUGUUUG

ACGUGULU

GGAGGACA

UCUUGGAG

ACtJUCUUG

GUUUCACA

GCCCAUUC

AACACACA

CAACACAC

CCAUCCUC

GGCCCUGG

GGUAGACA

CCAAGGUA

CUCCAAGG

AAGCCUCCC

CCUCCACA C

LJCCUCCACC

LJUGGCJCAC

:!CAC!ACT C 2CCACACU C

:UCCGAGCC

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 CUGAIJGA X MUGAUGA X UGAUGA X .7UGAUGA XC 'TGAUGA XC UGAUGA XC .7UGAUGA XC .TUGAUGA XC UTGAUGA X :UGAUGA XG 'TJGAUGA XG GAA AUAUAGGA GAA ACCACAGC GAA AGACCACA GAA AGUGAGAC GAA ACUGGUAG

GAA--AACUGGUA

GAA AGUCUUUU GAA AAGUCUUU GAA AAAGUCLU GAA AGUCCACG GAA ACAGAGUC GAA AGGACAGA GAA AGGUGCCG GAA AUCCAGUU GAA AGCAUUGC GAA AAGCAUU1G 3AA ACACACAA 'AA ACAUCUCA 3AA ACUCGGCC MA ACAGACUC 'AA~ AGACAGAC ,AA AGGUAGAC ;AA AGCCUCCA ;AA AAGCCUCC ;AA AGCCCGCA 'AA ACACUUGG 'AA AACACUJG A ACTJUGCGC

UCCUAUAU

GCUGUGGU

UGUGGUCU

GUCUCACU,

CUACCAGU

UACCAGMU

AAAAGACUI

AAAGACUUt

AAGACUUC(

CGUGGACUC

GACIJCUGUC

UCUGIJCCUC

CGGCACCUC

AACUGGAUC

GCAAUGCUU

CAAUGCUJU

UUGUGUGUU

UGAGAUGUC

GGCCGAGUC

GAGUCUGUC

GUCtJGUCUA

GUCIJACCUU

UGGAGGCUU

GGAGGCUU

UGCGGGCUA

CCAAGTJGUU

CAAGUGUUA

GCGCAAGUC

A AUGUGCCC C UCACUACC C ACUACCAG k CCAGUTJAA J AAAGCAAA k. AAGCAAAA J UCAAACAC J CAAACACG

AAACACGU

UGUCCUCC

CUCCAAGA

CAAGAAGU

UGUGAAAC

GAAUGGGC

rUGUGIJGUU

GUGUGLTUG

GAGGAUGG

CCAGGGCC

UGUCUACC

UACCUUGG

CCUUJGGAG

GGAGGCUU.

UGUGGAGG

GUGGAGGA

UGAGCCAA

AAGUGUGG

AGUGUGGG

GCUCGGAG

4815 CGCUCUCC CUGAUGA X GAA AGCGACUU AAGUCGCUC GGAGAGCG 145 4826 4844 4854 4870 4880 4908 4909 4913 4914 4915' 4923 4924 4932 4934 4935 4941 4946 4947 4957 4958 4969 4970 4971 4974 4977 4980 4989 4990 4993C

CAGGCUCC

GCCAGCAC

CUCCACCA

CAGGCCAC

CGUUUCCU

CAAAACCA

CCAAAACC

CCULJCCAA

ACCUUICCA

AACCUIJCC

AGCACGCA

GAGCACGC

ACUGIJGAA

CGACUGUG

CCGACUGU

UGUAACCC

UCGCCUGU

CUCGCCUG

CCACAGGG

GCCACAGG

GAGUAGGA

GGAGUAGG

.GGAGUAG

PUtAGGAGC

CUCAUUAGC

k.CUCUCAU 2CGGAAGGC

JCCGGAAGC

3AGUCCGGC CUGAUGA X GAA ACCGCUCU 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 ACCUUCCA 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 7UGAUGA X GAA AACGCCAC 7UGAUGA X GAA AAACGCCA :UGAUGA X GAA AGGAAACG .7UGAUGA X GAA AGUAGGAA :UGAUGA X GAA AGGAGUAG .UGAUGA X GAA ACUCUCAU UTGAUGA X GAA AACUCUCA UTGAUGA X GAA AGGAACUC

C

C

0 AGAGCGGUU

GGAGCCUG

AGAUGCAUU

GUGCUGGC.

UGCUGGCUC

UGGUGGAG

GGUGGGCUTJ

GUGGCCUG

UGGCCUGTJC

AGGAAACG

GGCAGGGTJU

UGGIJUUUG

GCAGGGUtJU

GGULTUUGG

GGUUUGGUU

UUGGAAGG

GUUUGGUTUU

UGGAAGGU

UUtJGGUUtJU GGAAGGU7U UGGAAGGUU

UGCGUGCU

GGAAGGUUU

GCGUGCUC

UGCGUGCUC

UUCACAGU

CGUGCUCUU

CACAGUCG

GUGCUCUUC

ACAGUCGG

UUCACAGUC

GGGUTJACA

AGUCGGGUU

ACAGGCGA

GUCGGGUUA

CAGGCGAG

AGGCGAGJU

CCCUGUGG

GGCGAGUUC

CCUGUGGC

UGUGGCGUU

UCCUACUC

GUGGCGUtJU

CCUACUCC

UGGCGUtUUC

CUACU.CCU

CGUULJCCUA

CUCCUAAU

UUCCUACUC CtJAAUGAG CUACUCCUA

AUGAGAGU

AUGAGAGUU

CCUUJCCGG

UGAGAGUTJC CUtJCCGGA GAGUUJCCUU

CCGGACUC

AGUEJCCUTJC

CGGACUCU

4994 AGAGUCCG CUGAUGA X GAA AAGGAACU 146 5001 ACACGUAA CUGAUGA X GAA AGUCCGGA 5003 AGACACGU CUGAUGA X *a.aa.

a a 5004 5010 5012 5046 5050 5053 5054 5057 5060 5062 5064 5076 5077 5080 5081 5105 5116 5135 5156 5162 5163 51642 5203 5211t 5212t 5214 1 5218 C 5229 U

GAGACACG

GGCCAGGA

CAGGCCAG

GAAGGAGC

!JGAGGAAG

AGAtJGAGG

GAGAUGAG

UGAGAGAU

GCCUGAGA

CAGCCUGA

CACAGCCU

UCUGAAUEJ

UUCUGAAU

GUGLUCUG

GGUGLTUCU

CCUCUGCC

CCCGUCAG

GUUCUCAC

GAAACCCU

CCAGCAGA

2CCAGCAG kCCCAGCAC kACCCUCAC JGACAGAG C

IUGACAGAC

LCUUGACA C

GCCACLU

rGAGCCL7iJ C CUGAUGA X CIJGAtJGA 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 CUGAUGA X CUGAUGA X CUGAUGA X UGAUGA X UGAUGA X UGAUGA X UGAUGA X .GAUGA XC UJGAUGA xC UGAUGA XC UTGAUGA XC UGAUGA XC UJGAUGA XC UGAUGA XC GAA AGAGUCCG GAA AAGAGUCC GAA ACACGUAA GAA AGACACGU GAA AGCTJGCAU GAA AGCAAGCU GAA AOGAGCAA GAA AAGGAGCA GAA AGGAAGGA GAA AUGAGGAA GAA AGAUGAGG GAA AGAGAUGA GAA AGGCACAG GAA AAGGCACA GAA AUTUAAGGC GAA AAUUAAGG GAA ACGUUCCU GAA AGCCUCUG GAA AUTUCUETJCG :;AA AGUUIJCUG 3AA ACCCTJGAG ,AA AACCCUGA ,AA AAACCCUG 'AA ACCUGCCA ;'AA ACCCUCAG 'AA AACCCUCA ;AA AGAACCCU ;AA ACAGAGAA IAA ACCGCCAC UCCGGACUC

UIJACGUGU

CGGACUCUU

ACGUGUCU

GGACUCUUA

CGUGUCUC

UJUACGUGUC

UCCUGGCC

ACGUGUCUC

CUGGCCUG

AUGCAGCUU GCUCCUtJC AGCUUGCUC

CUUCCUCA

UUGCUCCUU

CCUCAUCU

UGCUCCUTJC

CUCAIJCUC

UCCUUCCUC

AUCIJCUCA

UUCCUCAUC

UCUCAGGC

CCUCAtJCUC

UCAGGCUG

UCAUCUCUC

AGGCUGUG

CUGUGCCUU AAUUtCAGA UGUGCCtJUA

AUUCAGAA

GCCUtJAAUUJ

CAGAACAC

CCUUAATJUC

AGAACACC

AGGAACGUC

GGCAGAGG

CAGAGGCUC

CUGACGGG

CGAAGAALJU

GUGAGAAC

CAGAAACUC

AGGGUUUC

CtJCAGGGUtJ

UCUGCUGG

UCAGGGUTUU

CUGCUGGG

CAGGGUUJIC

UGCUGGGU

UGGCAGGUC

UGAGGGIU

CUGAGGGUU

CTJCUGUCA

tJGAGGGUUC

UCUGUCAA

AGGGUUCTJC

UGUCAAGU

UrTJCUCUGUC

AAGUGGCG

GUGGCGGUA AAGGCUCA 147 523~ 524' 524E 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 5339 5340 5344 5ACCAGCCU CUGATJGA X 1AGAGGAAG CUGAtJGA X 3 TAGAGGAA CUGAUGA X GAUAGAGG CUGAUGA X *AGAUAGAG CUGAUGA X *UGGAGAUA CUGAUGA X AGUGGAGA CUGAUGA X GGAGUGGA CUGAUGA X CAGGAGUG CUGAUGA X CCUGACAG CUGAUGA X GGGGGCCU CUGAUGA X AUACUGAG.CUGAUGA X AAAAUACU CUGAUGA X AGCUAAAA CUGAUGA X AAAGCUAA CUGAUGA X CAAAGCUA CUGAUGA X ACAAAGCU CUGAUGA X CACAAAGC CUGAUGA X AAGCCACA CUGAUGA X GAAGCCAC CUGAUGA X CCAUCAGG CUGAUGA X GCCAIJCAG CUGAUGA X CCAALUJAA CUGAUGA X AACCAAUU CUGAUGA X CAACCAAU CUGAUGA X AACCAACC CUGAUGA X AGCAAACC CUGAUGA X GGAGAGCA CUGAUGA X UGGAGAGC. CUGAUGA X UAUCUGGA CUGAUGA X GAA AGCCUUJUA GAA ACACCAGC GAA AAkCACCAG GAA AGAACACC GAA AAGAACAC GAA AGGAAGAA GAA AGAGGAAG GAA AUAGAGGA GAA AGAUAGAG GAA AGUGGAGA GAA ACAGGAGU GAA ACUULGGGG GAA AGGACUUG GAA ACUGAGGA GAA AUACUGAG GAA AAUACUGA GAA AA.AUACUG GAA AAAAUACU GAA AGCUAAAA GAA AAGCUAAA GAA AGCCACAA GAA AAGCCACA GAA AUUUTUUCU 3AA AGAUUUTU 3AA AAGAUUU 7AA AUUAAGAU 7AA ACCAALUJA ,AA ACCAACCA ,AA AACCAACC 3AA AGCAAACC

UAAAGGCUC

GCUGGUGUL

CUGGUGU1JC

GGUGUUCL

GUGUUCUUC

uucuuccUc

CUUCCUCIJA

UCCUCUAUC

CUCUAUCUC

UCUCCACUC

ACUCCUGUC

CCCCAAGUC

CAAGUCCUC

UCCUCAGUA

CUCAGUAUU

UCAGUAUJ

CAGUAUU-U

AGUALAUUUA

UUUUAGCUU

LTUUAGCULU

UUGUGGCUU

UGUGGCUtJC

AGAAAAAUC

AAAAAUCUU

AAAAUCUUA

AUCUUAALU

UAAUULGGUU

UGGUUGGUU

GGUUtGGUUTLJ

GGULTUGCUC

-AGGCUGGU

J CcCuuccU L7UCCUCUA J CCUCUAUC

CUCUAUCU

UAUCUCCA

UCUCCACU

UCCACUCC

CACUCCUG

CUGUCAGG

AGGCCCCC

CUCAGUAU

AGUAUUUU

UTJUAGCU

UUAGCUUUL

UAGCUUUG

AGCUULUGU

GCUUUJGUG

UGUGGCUU

GUGGCUUC

CCUGAUGG

CUGAUGGC

UUAAUTUGG

AAUTUGGLU

AUUTGGUTUG

GGUILJGGU

GGUUUGCU

UGCUCUCC

GCUCUCCA

UCCAGAUA

148 5346 AUUAUCUG CUGAUGA X GAA AGAGCAAA

C

C

5352 5355 5359 5367 5368 5369 5375 5376 10 5379 5380 5381 5382 5383 5392 5393 5398 5403 5405 5410 5412.

5415 5416 54171 54221 5423 5424 54251 5430

CUAGUGAU

UGGCUAGU

AAUCUGGC

AAULUCGA

UAALUUCG

GtJAALTUUC

UAAAAAGU

CUAAAAAG

CGGCUAAA

U2CGGCUAA

CLTCGGCUA

CCIJCGGCU

ACCUCGGC

GUUAUCAJ

UGUTUAUCA

GUAGAtJGU

AUACAGUA

GGAUACAG

CUAAAGGA

ULUCUAAAG

AAUUCUAC

AAAAUUCUC

LAAAAUUcC JAGGULJAA C kUAGGUTUAC JAUAGGEJU C -TUAUAGGU C JAGUUEJUA C CUGAULGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAIJGA 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 ZUGAUGA X MUGAUGA X 'UGAUGA X "UGAUGA X UGAUGA X UGAUGA X UGAUGA X .TJGAUGA X :UGAUGA x UGAUGA X *UGAUGA X GAA AUCUGGAG GAA AUUAUCUG GAA AGUGAUUA GAA AUCUGGCU GAA AAUCUGGC GAA AAAUCUGG GAA AUUtJCGAA GAA AATJUUCGA GAA AGUAALUU GAA AAGUAAUUT GAA AAAGUAAU GAA AAAAGUAA GAA AAAAAGUA GAA ACCUCGGC GAA AACCUCGG GAA AUCAUAAC GAA AUGUUAUC GAA AGAUGtJUA GAA ACAGUAGA GAA AUACAGUA GAA AGGAUACA GAA AAGGAUAC 3AA AAAGGAIJA 3AA AUUCTJAAA 3AA AALtUCUAA 3AA AAAUUCUA 3AA AAAAUUJCU 3AA AGGUTUAAA UUUGCUCUC CAGAUAAU CUCCAGAUA AUCACUAG CAGAUAAUC

ACUAGCCA

UAAUCACUA

GCCAGAUU

AGCCAGAUU UCGAAAUUr GCCAGAUUU CGAAAUTUA CCAGALUUC

GAAAUUAC

UUCGAAALTLJ ACUUTUUJA UCGAAAUUA CUUUUUAG AAAUUACUU

UUULAGCCG

AAUUACUUU TJJAGCCGA AUTUACUUUU UAGCCGAG UUTACUUUU AGCCGAGG UACUUUtJUA

GCCGAGGU

GCCGAGGUU AUGAUAAC CCGAGGUUA

UGAUAACA

GUULAUGAUA

ACAUCUAC

GAU2AACAUC

UACUGUAU

UAACAUCUA

CIJGUAUCC

UCUACUGUA

UCCUUJAG

UACUGUAUC

CUTJAGAA

UGUAUCCUU UAGAALUU GUAUCCUUU AGAAUUJU UAUCCJEJIA

GAAUUUUA

UUUAGAAUU UUAACCUA UUAGAAUJU UAACCUAU UAGAAUUUU

AACCUAUA

AGAAUUUJA ACCUAUAA UUUJTAACCUA

UAAAACUA

UAACCUAUA AAACUAUG 5432 CAUAGUTUU CUGAUGA X GAA AUAGGUUA 149 5438 AGUAGACA CUGAUGA X GAA AGUIJUUAU 5442 AACCAGUA CUGAUGA X GAA ACAUAGUU 5444 GAAACCAG CUGAUGA X GAA AGACAUAG 5450 CAGGCAGA CUGAUGA X GAA ACCAGUAG 5451 ACAGGCAG CUGAUGA X GAA AACCAGUA 5452 CACAGGCA CUGAUGA X GAA AAACCAGU AUAAAACUA UGUCUACU AACUAUGUC UACUGGUU CUAUGUCUA CUGGUUUIC CUACUGGUU UCUGCCUG UACUGGUUU CUGCCUGU ACUGGUUUC UGCCUGUG 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.

a a a a

S

a.

a a a. a S a a a a *5 a a S a* S. a. a *a a a a S a a a S. S 0 150 Tabe VI: oue flk-i VG Recep -Hairj Ribozymne and Substrate Sequences nt.

Posi.

t ion 74 88 105 110 125 132 138 175 199 309 342 434 630 655 739 HP Ribozyme Sequence Substrate GGGACACA AGAA GGGCCC

GUUAUCCC

GGAAUCGG

UCCGCGGA

CGGCUCUC

CCAGCCGC

CUGGCUCC

CAGCGCAA

GUCACAGA

CACAGAGC

CCCACAGA

UGCAAGUA

UAGACAUA

GAAUGGUG

AGAA GCGGGA AGAA GCCAGG AGAA GGUCAG AGAA GUGUCC AGAA GUCAGC AGAA GCGGCU AGAA GGGGAG AGAA

GUAUGG

AGAA GCUAGC kGAA

GCUCGG

IGAA GAAGGG kGAA GUGGAG ~GAA GUAAUC

ACCAGAGAACACACGJUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJYGUGGUACAUUACCUGGUA

ACCAGAGAACACACAGUJ1GUGGUACA1JJACCUGGUA ACCAGAGAAACACACGUJTGUGGUACAUrLACCUGGUA ACCAGAGAAACACACGUJ1GUGGUACAUJUACCUGGUA ACCAGAGAAZACACACGUUrGUGGUACAUJVACCUGGUA

ACCAGAGAACACACGJGUGGUACAJ.IACCUGGUA

ACCAGAGAAACACACGUJIGUGGUACAUJ.ACCUGGUA

ACCAGAGAAZACACACG1JUGUGGUACAUnJACCUGGUA

ACCAGAGAACACACAGUTGUGGUACAJ.LACCUGGUA

ACCAGAGAAZACACACGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUrGUGGUACAUJUACCUGGUA

ACCAGAGAAACACACGUJTGUGGUACAUJUACCUGGUA

ACCAGAGAA.ACACACGUUTGUGGUACAUJTLACCUGGUA

UCCCGCA

GCC

CCUGGCU

GAG

CUGACCC

GAU

GGACACC

GCU

GCUGACA

GCC

AGCCGCG

GCU

CUCCCCG

GUC

CCAUACC

GCC

GCUAGCU

GUC

CCGAGCC

GCC

CCCLJUCA

GAU

CUCCACU GUU1 GAUUACA

GAU

AUCCCCU

GCC

GGGAUAAC

CCGAUUCC

UCCGCGGA

GACAGCCG

GCGGCTJGG

L

0

GGAGCCAG

UTJGCGCUG

UCUGUGAC

GCUCUGUG

UCUGUGGG

UACIJUGCA

ZJAUGUCUA

ACCAUUC

3AGGGUCG CGACCCUC AGAA GGGGAU

ACCAGAGAAACACACGUUTGUGGUACAUUACCUGGUA

S. C.

~a S

S

**S

C

5 C C C S. S

S.,

S..

S

CC C CS C S *C S S. *e *500* S C C. C C C C CC C C CCC C 0 151 807 920 1002 1229 1365 1556 1629 1687 1696 1796 1950 1953 1985 2055 2082 2208 2252 2444

CUGUUUCC

ACAUGAUA

UU1JUCUCC UCUtIGAUC

AUAUCAGG

UCUCACCG

UUGGCGUA

UCUGUAGG

UUGGCCGG

UUCCUUCA

GGCUGGGC

GUUGGCUG

CAGUCCAC

CCCAUGUG

UUCUUGCA

UUIAUCUUTG

GGAUGAUG

UGCGGAUA

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

GGCUUC

GUAGGA

GGGCAU

GGuuGC

GCAGGU

GGGACA

GAUGU

GGUGUG

GAGCAA

GUUUGA

GGUUCC

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACATJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

UGTJUCCG

CCUAUCA

GCUAUCU

GUGGACG

UUACCCA

CACCCCA

AUCCACA

GAAGCCU

UCCUACA

AUGCCCU

C CAA CC U

ACCUGCU

UGUCCCU

AACAUCG

CACACCA

UUGCUCU

UCAAACA

GGAACCU

GAU

GUC

GCC

GAU

GCU

GAU

GUC

GCU

GAC

GAU

GCU

GCC

GUU

GUC

GU

GCU

GCU

GAC

GGAAACAG

UAUCAUGU

GGAGAAAA

GAUCAAGA

CCUGAUAU

CGGUGAGA

UACGCCAA

CCUACAGA

CCGGCCAA

UGAAGGAA

GCCCAGCC

CAGCCAAC

GUGCACUG.

CACAUGGG

UGCAAGAA

CAAGAUAA

CAUCAUCC

UAUCCGCA

2639 GCUUAACG AGAA GUAGGA ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA UCAGGCCUAG UCCUACG GAC CGUUAAGC 0 152 2703 2777 2832 3199 3278 3304 3421 3450 3475 3663 3689 3703 3860 3873 4038 4181 4196 4212

GGCAAUUC

CUAGUUUC

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

AGAA

AGAA

AGAA

AGAA

AGAA

GGAUCC

GGUCCC

GCCUCA

GGCAGA

GGAAGU

GUAACA

GAAGUC

GGGUCU

GGCAUC

GGAGCC

GGUACA

GUCCAG

GGGAGA

GGUGAG

GGGAUC

GGUUGG

GGUAGC

GAGUGA

ACcAGAGAAACACACGUUGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUG-GUA

ACCAGAGAAACACACGUUTGUGGUACAUU~ACCUGGUA

ACCAGAGAAACACACGUJIGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGJT.GUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACG

UUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAJTUACCUGGUA

GGAUCCA

GGGACCG

UGAGGCA

UCUGCCA

ACIJUCCU

UGUUACA

GACUUCG

AGACCCG

GAUGCCC

GGCUCCU

UGUACCA

CUGGACU

UcUCCCU

CUCACCU

GAUCCCA

C CAA CCA

GCUACCA

GAU

GCU

GAC

GCU

GAC

GCU

GCU

GAU

GAC

GAC

GAC

GCU

GCC

GUU

GAU

GAC

GUC

GAAIJUGCC

GAAACUAG

GCtJUUUGG

CAGGCUUU

CUUGGAGC

UCCAAGUG

UGGCCCGG

UAUGUCAG

UCCCUUIJG

UACACUAC

CAUGCUGG

GGCAUGAG

UACCUCAC

UCCUGUAU

GACAGCCA

CAGUGGCU

UGGGUAUC

4278 UCAGCGUG AGAA GCAGCA ACCAGAGAAACACACGUJGUGGUACAJTUACCUGGUA UGCUGCA GUU CACGCUGA 01 1S3 4287 GUCCCUGA AGAA GCGUGA ACAAAAAAGUGGUCUACGU UCACGCU GAC UCAGGGAC 4307 4318 4338 4344 4349 4383 4462 4574 4626 4723 4823 4836 4896 4938 4996 5042 5118 5165

AGGAGGUG

UCCAUUUA

GGAGCCGG

GGGGGCGG

GAGUUGGG

AAAAUCUA

UCCUUGCA

GAGACCAC

UCUUGGAG

CCAAGGUA

CAGGCUCC

CACAAUGC

ACCCUGCC

UGUAACCC

ACGUAAGA

AAGGAGCA

UCGGCCCC

CUCCACCC

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCAGUG

GGAGGU

GGACCA

GGGACA

GAGCCG

GCACCU

GAGGUC

GGGCAC

GAGUCC

GACUCG

GCUCUC

GCAGGC

GCCUUU

GUGAAG

GGAAGG

GCAUCA

GGAGCC

GAAACC

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUJIGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUU.GUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACAAAAAAGUGGUCUACGU

ACCAGAGAAACACACGJT.GUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

CACUGCA

ACCUCCU

UGGUCCU

UGUCCCG

CGGCUCC

AGGUGCU

GACCUCA

GUGCCCU

GGACUCU

CGAGUCU

GAGAGCG

GCCUGCA

AAAGGCG

CUUCACA

CCUJUCCG

UGAUGCA

GGCUCCU

GGUUtJCU

GCU

GUU

GUC

GCU

GCC

GCU

GAC

GCU

GUC

GUC

GUtJ

GAU

GCC

GUC

GAC

GCU

GAC

GCU

CACCUCCU

UAAAUGGA

CCGGCUCC

CCGCCCCC

CCCAACUC

UAGAUUU

UGCAAGGA

GUGGUCUC

CUCCAAGA

UACCUUGG

GGAGCCUG

GCAUUGUG

GGCAGGGU

GGGUUACA

UCUUACGU

UGCUCCUU

GGGGCCGA

GGGUGGAG

154 5310 5363 545i UUUCUGCC AGAA GGAAGC ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA AUUUCGAA AGAA GGCUAG ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA AGCACACA AGAA GAAACC ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA GCIJUCCU GAU GGCAGAAA CUAGCCA CAU UUCGAAAU GGUUUCU GCC UGUGUGCU 155 Table VIII: Mouse fit-i VEGF Receptor-Hammerhead Ribozvrne arnd Substrate Seauence HH Ribozyme Sequence Subs trate Posi 9 tion 17 19 23 32 10 53 61 71 15 78 83 84 86 94 20 100 106 112 113 132 133 134 152 171 173 175 176 177

GUGAGCAA

UGGUGAGC

ACCAUGGU

CAGCAGCU

UAAGGCAA

CGUAAGGC

CAGCGCGU

GCAGCGCG

AGACACCC

GAGAAGCA

CCUGUGAG

UCCUGIJGA

UAUCCUGU

CUGAGCCA

UCGACCCU

UTUAACUTUC

GCACUUUU

GGCACIUU

GCCtUtJA

UGCCUUUU

GUGCCUUU

GCITJUGCAU

GAGAAAGA

UUGAGAAA

ACUtJGAGA

CACUUGAG

GCACUTUGA

CUGAUGA X GAA ACGCGGCC

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 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 ACUCAGUJ GAA AACUCAGU GAA AAACUCAG GAA ACAUGCUG GAA AGUCUGGC GAA AGAGUCUG GAA AGAGAGUC GAA AAGAGAGU GAA AAAGAGAG

CCGCGUCUU

GUCUUGCUC

ACCAUGGUC

ACCGCGGUC

CGCGGUCUU

UCUUGCCUU

CUUGCCUUA

GCGCUGCUC

UCGGGUGUC

UGUCUGCUU

GUCUGCUUC

CUGCJTLCUC

CACAGGAUA

AUAUGGCUC

CUCAGGGUC

GUCGAAGIJ

UCGAAGUUA

AACUGAGUU

ACUGAGUUU

CUGAGUUUA

CAGCAUGUC

GCCAGACUC

CAGACUCUC.

GACUCUCUU

ACUCUCUUU

CUCUCUUUC

GCUCACCA

ACCAUGGU

AGCUGCUG

UUGCCUUA

GCCUUACG

ACGCGCUG

CGCGCUGC

GGGUGUCU

UGCUTUCUC

CUCACAGG

UCACAGGA

ACAGGAUA

UGGCUCAG

AGGGUCGA

GAAGUUAA

AAAAGUGC

AAAGUGCC

UAAAAGGC

AAAAGGCA

AAAGGCAC

AUGCAAGC

UCUTUUCU.C

UTUUCUCAA

UCUCAAGU

CUCAAGUG

UCAAGUGC

GGCCGCGUC UUGCUCAC 156 179 CUGCACULJ CUGAUGA X GAA AGAAAGAG CUCIJUUCUC AAGUGCAG 205 211 213 254 258 265 282 292 293 304 310 341 343 15 351 355 359 363 367 20 369 372 373 394 396 397 401 403 407 409 410 413 414 429

GAGACCAI

UGGGCAG

4

CGUGGGC

GGGGGAGI

CGAUGGGC

CACAGG C UUtGCCUGI

UGCUGCAC

GUGCUGU.

CCAAGGUC

CCGUGUCC

CAGGUGUA

UACAGGUG

GAGGUAUC

UAGGGAGG

GAUGUAGG

AGUAGAUG

UCGAAGUA

CUTLJCGAAG

UUUCLTUCG

UUUTCUEJC

AGAULJGAA

GUAGAUUG

UGUAGALUJ

AAUAUGUA

CAAAUAUG

CUAACAAA

CACUAACA

UCACUAAC

GCAUCACU

UGCAUCAC

UAUGAAAG

U3 CUGAUGA k. CUGAUGA

CUGAUGA

J CUGAUGA 3 CUGAUGA

'CUGAUGA

JCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA)

CUGAUGA)

CUGAUGA)

CUGAUGA Y CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X X GAA AGUGGGCU X GAA ACCAUGAG K GAA AGACCAUG K GAA AUGCUCAG GAA AGUGAUGC C GAA AUGGGGGA IGAA AUCCCUCC GAA AUUGCCUG GAA AAUUGCCU GAA AGGUGCUG GAA AGGUCAAG GAA AGGCCCGU GAA AGAGGCCC GAA ACAGGUGU GAA AUCUACAG GAA AGGUAUCU GAA AGGGAGGU GAA AUGUAGGG GAA AGAUGUAG GAA A.GUAGAUG GAA AAGUAGAU GAA AUUCCGCU GAA AGAUUCCG GAA AAGAUUCC GAA AUUGAAGA GAA AGAUTUGAA GAA AUGUAGAU GAA AUAUGUAG GAA AAUAUGUA GAA ACAAAUAU GAA AACAAAUA GAA ACUCCCUG

AGCCCACTJ

CUCAUGGUJ

CAUGGUCU

CUGAGCAU

GCAUCACU

UCCCCCAU

GGAGGGAU

CAGGCAAtfl

AGGCAAUU(

CAGCACCUIT

CUUGACCUE

ACGGGCCUC

GGGCCUCUI

ACACCUGU.P

CUGUAGAUPJ

AGAUACCUC

ACCUCCCUA

CCCUACAUC

CUACAUCUA

CAUCUACUU

AUCUACUUC

AGCGGAAUC

CGGAAUCUU

GGAAUCUUIC

UCUUCAAUC

UUCAAUCUA

AUCUACAUA

CUACAUAUU

UACAUAULTU

AUAUUUGUU

UAUUUGUUA

CAGGGAGUC

'C AUGGUCJC 'C UCUGCCCA C UGCCCACG C ACUCCCcC C CCCCAUCG C GGCCUGUG k. ACAGGCAA J CUGCAGCA

-UGCAGCAC

J GACCUJGG

JGGACACGG

7UACACCUG

LCACCUGUA

LGAUACCUC

CCUCCCUA

CCUACAUC

CAUCUACU

UACUUCGA

CUUCGAAG

CGAAGAAA

GAAGAAAA

UUCAAUCU

CAAUCUAC

AAUCUACA

UACAUAU

CAUAUUUG

UUUGUUTAG

UGUUAGUG

GUUAGUGA

AGUGAUGC

GUGAUGCA

CULTUCAUA

157 432 CUCUATJGA CUGAUGA X GAA AGGACUCC GGAGUCCUU UCAUAGAG

S

433 434 43.7 455 464 491 494 497 514 524 530 536 544 545 546 550 551 555 20 558 560 561 581 594 604 605 606 608 611 625 635 662 676

UCUCUAUC

AUCUCUAL

UGCAUCUC

AGLUUGGG

AUGUGCAC

GGGAUGAU

CAGGGGAU

CGGCAGGG

CGUUGGGU

GUGACUGU

UUUAGGGU

AACUUU

CAAAUGGA

UCAAAUGG

AUCAAAUG

GAGUAUCA

AGAGUAUC

GGUAAGAG

AGGGGUAA

UCAGGGGU

AUCAGGGG

UCCCAUGU

GCCUCUCC

CUAUUAUA

GCUAUUAU

UGCUAL1UA

UTUUGCUAU

GCAUUUGC

UCUCTJUUG

AGCAGUCC

UGCCCGUU

UUGUCUGG

;CUGAUGA

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

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

GAA AAGGACUC GAA AAAGGACU GAA AUGAAAGG GAA AUGUCAGU GAA AGUUUGGG GAA AGCUGUCU GAA AUGAGCUG GAA AUGAUGAG GAA ACGUCACC GAA ACGUUGGG GAA ACUGUGAC GAA AGGGUGAC GAA ACLJUUUUU GAA AACUUUUU GAA AAACUUJU GAA AUGGAAAC.

GAA AAUGGAAA GAA AUCAAAUG GAA AGUAUCAA GAA AGAGUAUC GAA AAGAGUAU GAA AUUCUUUG GAA ACUGUCCC GAA AGCCUCUC GAA AAGCCUCU GAA AAAGCCUC GAA AUAAAGCC GAA AUUAUAAA GAA ACGUUGCA GAA AUCUCUUU GAA ACGGUGGC GAA ACAGGUGC GAGUCCUtJL

AGUCCUUUC

CCUUUCAU;

ACUGACAUP

CCCAAACUL

AGACAGCUC

CAGCUCAUC

CUCAUCAUC

GGUGACGUC

CCCAACGUC

GUCACAGUC

GUCACCCUA

AAAAAAGUUJ

AAAAAGUU

AAAAGUTUUC

GUU-UCCAUU

UUUCCAUUU

CAUUUGAUA

ULJGAUACUC

GAUACUCUJ

AUACUCUUA

CAAAGAAUA

GGGACAGUA

GAGAGGCUU

AGAGGCUUU

GAGGCUUJA

GGCUTUUAUA

UUIJAUAAUA

UGCAACGUA

AAAGAGAUA

GCCACCGUC

GCACCUGUA

J CAUAGAGA

AUAGAGAU

GAGAUGCA

CCCAAACU

GUGCACAU

AUCAUCCC

AUCCCCUG

CCCUGCCG

ACCCAACG

ACAGUCAC

ACCCUAAA

AAAAAGUU

UCCAUUEJG

CCALUU.GA

CAULTUGAU

UGAUACUC

GAUACUCU

CUCLTOACC

UUACCCCU

ACCCCUGA

CCCCUGAU

ACAUGGGA

GGAGAGGC

UAUAAUAG

AUAAUAGC

UAAUAGCA

AUAGCAAA

GCAAAUGC

CAAAGAGA

GGiCUGCU

AACGGGCA

CCAGACAA

158 688 GGGUCAGA CUGAUGA X GAA AGUUUGUC GACAAACUA UCUGACCC 690 699 711 716 719 725 731 758 771 773 776 779 803 15 807 831 832 840 849 859 861 863 875 888 889 904 905 914 915 917 918 923 953

AUGGGUC

GGUCUGC

UAGGAU

ACAUCUAi

UGGACAU

CGUAJUU(

GGCGGGC(

UGCCCGUC

GAGGACA;

UUGAGGAC

CAGUUGAC

GUGCAGUL

CUCGUAUL

CACCCUCG-

ACCAGGG U

UACCAGGG

AGUUGCUU

UGCUCUCU

GCCUUAUA

CUGCCUUA

CGCUGCCU

CUCCGGUC

GUUGUGGG

UGUUGUGG

CACUGUGG

ACACUGUG

AUCUtTAAG

GAUCUUAA

UUGAUCUU

GUUGAUCU

ACAUUGUU

CAGGUGUA

A CUGAUGA C CUGAUGA S CUGAUGA

CUGAUGA

2CUGAUGA 3CUGAUGA

CUGAUGA

3CUGAUGA k CUGAUGA

CUGAUGA

CUGAUGA

ICUGAUGA

fCUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA2

CUGAUGA

CtJGAUGA

CUGAUGA

CUGAUGA Y~ CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X K GAA AUAGUUUG K GAA AUGGGUCA GAA AUUGGUCU C GAA AUTUGUAUU C GAA AGGAUUGU IGAA ACAUCUAG GAA AUUUGGAC GAA AGCAGUCU GAA AGUCUGCC GAA AGAGUCUG GAA ACAAGAGU GAA AGGACAAG GAA AGCUCCGU GAA AUUGAGCU GAA AUTUCCAGC GAA AAUTUCCAG GAA ACCAGGGU GAA AGUUGCUU GAA AUGCUCUC GAA AGAUGCUC GAA AUAGAUGC GAA AUCCGCUG GAA AUGGCUCC GAA AAUGGCUC GAA ACACAUJG GAA AACACAUU GAA ACACUGUG GAA AACACUGU GAA AGAACACU GAA AAGAACAC GAA AUCUUAAG

CAAACUAU

UGACCCAU,

AGACCAAU,

AAUACAAU(

ACAAUCCUj

CUAGAUGU(

GUCCAAAU)

AGACUGCUC

GGCAGACUC

CAGACUCUL

ACUCUUGUC

CUUGUCCUC

ACGGAGCUC

AGCUCAAUA

GCUGGAAUU

CUGGAAUTUA

ACCCUGGUA

AAGCAACUA

GAGAGCAUC

GAGCAUCUA

GCAUCUAUA

CAGCGGAUU

GGAGCCAUU

GAGCCAUtJC

CAAUGUGUU

AAUGUGIJUC

CACAGUGUU

ACAGUGLUC

AGUGUUCUU

GUGUTUCUUA

CUUAAGAUC

C UGACCCAU C GGCAGACC k. CAAUCCUA

CUAGAUGU

k' GAUGUCCA

:CAAAUACG

k. CGCCCGCC 7CACGGGCA

LTUGUCCUC

JGUCCUCAA

CUCAACUG

AACUGCAC

AAUACGAG

CGAGGGUG

ACCCUGGU

CCCUGGUA

AAGCAACU

AGAGAGCA

UAUAAGGC

UAAGGCAG

AGGCAGCG

GACCGGAG

CCCACAAC

CCACAACA

CCACAGUG

CA CAGUGU

CUUAAGAU

UUAAGAUC

AAGAUCAA

AGAUCAAC

AACAAUGU

CUGAUGA X GAA AGCCCCUU AAGGGGCUC

UACACCUG

159 a a a *aaaa.

a a a 955 963 979 982 985 986 991 993 994 995 1003 1015 1027 1028 15 1031 1044 1084 1087 1089 20 1096 1114 1115 1120 1130 1133 1138 1139 1150 1162 1168 1173 1177 1179

GACAGGUC

CUUCACG(

GGAACGAC

ACUGGAAC

AAGACUGC

AAAGACUC

UGUUTGAAP

GGUGUEJG.P

AGGUGUIJC

GAGGUGUU

CAUGCACG

CUUUUUCA

CACUGAUG

ACACUGAU

UUCACACU

CUGCTJUCC

GCCGAUAG

ACAGCCGA

GGACAGCC

CUUTUCAUG

GGGAGGGG

GGGGAGGG

UTUUCUGGG

AACCAUAC

UUAACCA

CAUCUUUU

CCAUCUUU

UJUGCAGGC

CAGACUUC

AGCGAGCA

CAAAUAGC

GUACCAAA

AUGUACCA

3CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

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

*GAA AGAGCCCC GAA ACAGGUGU *GAA ACCCACUC GAA AGGACCCA GAA ACGAGGAC GAA AACGAGGA GAA ACUGGAAC GAA AGACUGGA GAA AAGACUGG GAA AAAGACUG GAA AGGUGUUG GAA ACACAUGC GAA AUCCUUUU GAA AAUCCUUU GAA AUGAAUCC GAA AUGtJUUCA GAA ACCGUCUU GAA AGGACCGU GAA AUAGGACC GAA ACAGCCGA GAA AGGCCUUC GAA AAGGCCUU GAA AGGGGAAG GAA AUUUCUGG GAA ACGAULTUC GAA ACCAUACG GAA AACCAUAC GAA AGCCAUCU GAA AUGUUGCA GAA ACUUCAAU GAA AGCAGACU GAA AGCGAGCA GAA AUAGCGAG

GGGGCUCU)

ACACCUGUC

GAGUGGGU(

UGGGUCCUC

GUCCUCGUL

UCCUCGUUC

GUUCCAGUC

UCCAGUCUL

CCAGUCULTUI

CAGUCUUtJC

CAACACCUC

GCAUGUGUA

AAAAGGAUU

AAAGGAUUC

GGAUTUCAUC

UGAAACAUC

AAGACGGUC

ACGGUCCUA

GGUCCUAUC

UCGGCUGUC

GAAGGCCUU

AAGGCCUJUC

CUUCCCCUC

CCAGAAAUC

GAAAUCGUA

CGUAUGGUJ

GUAUGGUUA

AGAUGGCUC

UGCAACAUU

AUUGAAGUC

AGUCUGCUC

UGCUCGCUA

CUCGCUAUU

k CACCUGUC

'GCGUGAAG

CUCGUUCC

GLTUCCAGU

J CCAGUCUU

CAGUCULTLJ

UtJUCAACA rUCAACACC ICAA.CArCCU

AACACCUC

CGUGCAUG

UGAAAAAG

CAUCAGUG

AUCAGUGU

AGUGUGAA

GGAAGCAG

CUAUCGGC

UCGGCUGU

GGCUGUCC

CAUGAAAG

CCCCUCcC ccuCcCc

CCCAGAAA

GUAUGGU

UGGLUAAA

AAAAGAUG

AAAGAUGG

GCCUGCAA

GAAGUCUG

UGCUCGCU

GCUAUUUG

UUUGGUAC

UGGUACAU

160 9 9.

9 *99* 9 9 9 *999 9* *9 1180 1184 1192 1195 1198 1199 1202 1203 1205 1237 1239 1244 1246 1256 15 1264 1271 1273 1274 1275 1283 1293 1295 1298 1301 1314 1319 1321 1330 1336 1339 1343 1344

CAUGUAC

UAGCCAU

ILTUAAUGA

UAAtJUAA

UGAUAAU

UUGAUAAI

UCtUUGAI

AUCUUUG

ACAUCUMt

AGAUCGUI

CAAGAUCC

CC CAG CA7

UGCCCAGC

GACUGCUL

AUAGCCUC

UULTUUAAA

GGUUUUUA

AGGUUUUUJ

GAGGUUU

GUGGCAGU

UACAAUGA

tUUACAAU

ACGUUAC

UTUCACGUU

GUAGAUCU

UUUUCGUA

ACUUUEJCG

AGGACACG

GAAGCGAG

UUGGAAGC

GGGCUtJGG

UGGGCUUG

'C CUGAUGA G CUGAUGA G CUGAUGA U CUGAUGA U CUGAUGA LJ CUGAUGA J CUGAUGA

CUGAUGA

J CUGAUGA k CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

TCUGAUGA

rCUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGAI

CUGAUGA2

CUGAUGA)

CUGAUGA

CtJGAUGA 2 CUGAUGA Y CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA

X

X GAA AAUAGCGA X GAA ACCAAAUA X GAA AGCCAUGU X GAA AGUAGCCA X GAA AUGAGUAG K GAA AAUGAGUA K GAA AUUAAUGA K GAA AAUUAAUG SGAA AUAAUUAA CGAA AGUCCCCU C GAA AUAGUCCC GAA AUCGUAUA GAA AGAUCGUA GAA AUGCCCAG GAA ACUGCUUU GAA AGCCUUGA GAA AUAGCCUU GAA AAUAGCCU GAA AAAUAGCC GAA AGGUUUEJU GAA AGUGGCAG GAA AGAGUGGC GAA AUGAGAGU GAA ACAAUGAG GAA AGGUJUUCA GAA AUCUGAGG GAA AGAUCUGA GAA ACUtUUCG GAA ACACGGAC GAA AGGACACG GAA AGCGAGGA GAA AAGCGAGG

UCGCUAUU

UAUUUGGU

ACAUGG CU

UGGCUACU

CUACUCAU

UACUCAUUj

UCAUUIAALUE

CAUUAAUU)

UUAAUUAU(

AGGGGACTJ;

GGGACUAU;

tJAUACGAUC

UACGAUCUU

CUGGGCAUA

AAAGCAGUC

UCAAGGCUA

AAGGCUAUUT

AGGCUAUUU

GGCUAUUA

AAAAACCUC

CUGCCACUC

GCCACUCUC

ACUCUCAUU

CUCALTTJGUA

UGAAACCUC

CCUCAGAUC

UCAGAUCUA

CGAAAAGUC

GUCCGtJGUC

CGUGUCCJC

UCCUCGCUU

CCUCGCTUC

U GGUACAUG.

A CAUGGCUA h CUCAUUAA C AUUAAtIUA 'J AAUUAUCA

AUUAUCAA

J AUCAAAGA

UCAAAGAU

AAAGAUGU

UACGAUCU

CGAUI=G

UUGCUGGG

GCUGGGCA

AAGCAGUC

AAGGCUAU

UUUAAAAA

UAAAAACC

AAAAACCU

AAAACCUC

ACUGCCAC

UCAUTUGUA

AUTUGUAAA

GUAAACGU

AACGUGAA

AGAUCUAC

UACGAAAA

CGAAAAGU

CGUGUCCU

CUCGCUUTC

GCUTUCCAA

CCAAGCCC

1356 CGGAUAGA CUGAUGA X GAA AGGUGCGC GCCCACCUC UCUAUCCG 161 add.

ad 0 a data o *040 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 1S78 1586

AGCGGAU,

CCAGCGG,

GCCCAGC(

CAAGUGA(

GUGCAAGI

CACGGUG(

GGAUGCC2

GGCCGAGC

UGUUGGCC

AGCCACGT.

GGGUGCC;

AUUGUGGT.

UUUGGAGL

UUUCUUrJG

AGAAGUCA

CAGUGCAG

UCAGUGCA

GGAUAAAG

CCAGGAUA

UCCAGGAU

AUCCAGGA

GGAUCCAG

GCUGCUGG

UGUU'UCCU

CUGUUtJCC

AUGCUCUC

CGCUGAGA

UGCGCUGA

CAUGCGCU

CCUUCUAU

GUUCCUTUC

AACCGUCU

AAUGUGCU

P, CUGAUGA k. CUGAUGA 3 CUGAUGA 3CUGAUGA J CUGAUGA

CUGAUGA

k. CUGAUGA

CUGAUGA

CUGAUGA

J CUGAUGA

LCUGAUGA

rCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA 2

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I~ CUGAUGA Y CUGAUGA Y K GAA AGAGGUGG K GAA AGAGAGGU K GAA AUAGAGAG K GAA ACUUGUCU GAA AGGACUUG C GAA AGUGAGGA C GAA ACACGGUG IGAA AUG CCAUA GAA AGGGAUGC GAA AUTUGUUGG GAA AGCCACGU *GAA ACAGGGGU *GAA AUUGUGGU *GAA AGUGAtJUG GAA ACCUUTUCU GAA AGUCAUAC GAA AAGUCAUA GAA AUUCUUCA GAA AGGAUtJCU GAA AAGGAUJTJC GAA AAAGGAU GAA AUAAAGGA GAA AUCCAGGA GAA AGUUGCUG GAA AAGUUGCU GAA AUTUCUGUU GAA AUGCUCUC GAA AGAUGCUC GAA AGAGAUGC GAA ACCGUCAU GAA AUGACCGU GAA AIJUUGUUC GAA ACCGUCUU

CCACCUCU(

ACCUCUCUJ

CUCUCUAU(

AGACAAGUC

CAAGUCCUC

UCCUCACU.

CACCGUGU;

UAUGGCAUC

GCAUCCCUC

CCAACAAUC

ACGUGGCUC

ACCCCUGUC

ACCACAAUC

CAAUCACUC

AGAAAGGUA

GUAUGACUU

UAUGACUUC

UGAAGAAUC

AGAAUCCUU

GAAUCCUU

AAUCCUTUUA

UCCUUtJAUC

UCCUGGAUC

CAGCAACUU

AGCAACUUA

AACAGAAUU

GAGAGCAUC

GAG CAUCUC

GCAUCUCUC

AUGACGGUC

ACGGUCAUA

GAACAAAUA

AAGACGGUU

UAUCCGCU

SUCCGCUGG

:CGCUGGGC

:CUCACUJG

ACUUGCAC

JGCACCGUG

UGGCAUCC

CCUCGGCC

GGCCAACA

ACGUGGCU

UGGCACCC

ACCACAAU

ACUCCAAA

CAAAGAAA

UGACUTUCJ

CUGCACJG

UGCACUGA

CUUUAUCC

UAUCCUGG

AUCCUGGA

UCCUGGAU

CUGGAUCC

CCAGCAGC

AGGAAACA

GGAAACAG

GAGAGCAU

UCUCAGCG

UCAGCGCA

AGCGCAUG

AUAGAAGG

GAAGGAAC

AGACGGtU

AGCACAUTJ

162 1587 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 1800

CAAUGUG

CCACCAC

GGGUCUG

AGGGGUC

CAGCUGU

GGCAGCU

UUUUAUU(

ALUUUAUI

CCCUAULT(

ACAGUCCC

UAAAAUTIt

UGACAUA;Z

GUGACAU;

UGUGACAL

CUGUGACPA

ACAUCUGlU

AAACGUGA

GAAACGUG

GGAAACGU

UCCAAGGA

UUCCAAGG

UUUCCAAG

UCUUUUcc

CCACACAG

AAUTUUAUU

CAGGAAUU

UGUACAGG

CUGUACAG

UGUCUCUG

AucCAGGU

AAUCCAGG

CGUAGCAG

CCGUAGCA

C CUGAUGA C CUGAUGA A. CUGAUGA U CUGAUGA P, CUGAUGA "a CUGAUGA 3 CUGAUGA J CUGAUGA J CUGAUGA

-CUGAUGA

JCUGAUGA

CUGAUGA

LCUGAUGA

ICUGAUGA:

LCUGAUGA

fCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA2

CUGAUGA)

CUGAUGA)

CUGAUGA 2 CUGAUGA Y~ CUGAUGA Y~ CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CtJGAUGA X CUGAUGA X CUGAUGA X X GAA AACCGUCU X GAA AUGUGCUA X GAP. AGUCAGCC X GAA AGAGUCAG K GAP. AUUCCAGG K GA. AGAUUCCA K GA. AGGCCCGG SGA. AAGGCCCG C GA. AUUGAAGG C GAP. AUUUTUAUU CGAP. AUGtJUUCU GAP. AUUUUAUG GAP. AAUUUUAU GA. AAAUULTUA GAP. AAAApjrji GAA ACAUAAAA GA. AGCCAUUC GAP. AAGCCAUJ GAA AAAGCCAU GAP. ACGUGAAAP GA. AACGUGA.

GAP. AAACGUGA GAP. AGGAAACG GAP. ACAGUUUC GAP. ACCACACA GAP. AUTUGACCA GAP. AUUTUAUTUG GAP. AAUUUAUU GAP. ACAGGAAU GAP. AUGUCUCU GAP. AAUGUCUC GAP. AUCCAGGU GAP. AAUCCAGG

AGACGGLU

UAGCACAU

GGCUGACU

CUGACUCU

CCUGGAAU

UGGAAUCUM

CCGGGCCLII

CGGGCCUU(

CCUYUCAP.U)

AP.UAAAAUI

AGAAACAtJI

CAUAA.AUL

AUAAAAUUL

UAP.AAUUUL

AP.AAULTUUA

UUUUATJGUC

GAAUGGCUU

AP.UGGCUUU

AUGGCUUUC

UTUUCACGUU

UUCACGUUUTL

UCACGUUUTC

CGUUUCCUU

GAA ACUGUC

UGUGUGGUC

UGGUCAAUA

CAP.UAAP.UU

AP.UAAAUUC

AUUCCUGUA

AGAGACAUJI

GAGACAUJA

ACCUGGAUU

CCUGGAUuc A. GCACAUUG U GGUGGUGG C UCAGACCC C AGACCCCU

UACAGCUG

k. CAGCUGCC J CAAUAAA.

:AAUAAAAu kAAAUAGGG kGGGACUGU

AAAUUUUA

Y UUAUGUCA

TUAUGUCAC

fAUGUCACA

UGUCACAG

ACAGAUGU

UCACGULU

CACGUUTUC

ACGUUUCC

UCCUUGGA

CCUUGGAA

CUUGGAAA

GGAAAAGA

CUGUGUGG

AAUAAAUU

AAUTUCCUG

CCUGtJACA

CUGUACAG

CAGAGACA

ACCUGGAU

CCUGGAUU

CUGCUACG

UGCUACGG

163 1805 ACUGUCCG CUGAUGA X GAA AGCAGAAU AUUtCUGCUA CGGACAGU 1814 1815 1836 1839 1841 1866 1872 1873 1876 1880 1884 1892 1895 1898 1909 1911 1913 1921 1930 1952 1954 1970 1973 1974 1988 1989 1991 1994 1995 2001 2002 2021 CUGUTUGU1

UCUGUUGI

GCUGAUAC

CLUUGCUG]

UGCUTUGCL

GUAAUCUL

GAUGGAGt.

UGAUGGAG.

GAGUGAUC

UTUCAGAGU

AAGGUUCA)

UUGAUGAC

UTUCUTUGAU

ACGUUCUEJ

CUUCUAGA

GUCUUCUA

GAGUCUUC

AGGUGCCC

UGCACGCA

CCUGUGUA

CCCCUGUG

UTUCCGAAG

GUCUUCCG

UGUCUUCC

CUAACGAG

UCTJAACGA

UCUCUAAC

GAAUCUCU

CGAAUCUC

CGCUUCCG

GCGCUUCC

AGGUUUEIJG

J CUGAUGA J CUGAUGA

CUGAUGA

SCUGAUGA

JCUGAUGA

J CUGAUGA T CUGAUGA

;CUGAUGA

CUGAUGA

FCUGAUGA

*CUGAUGA

*CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA

CUGAUGA2 CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA Y GAA ACUGUCCG GAA AACUGUCC *GAA AUGGUGCA *GAA ACUAUGGU *GAA AUACUAUG GAA AGUGGUGG GAA AUCUUGAG GAA AAUCUUGA GAA AGUAAUCU GAA AUGGAGUA GAA AGUGAUGG GAA AGGUUCAG GAA ACAAGGU GAA AUGACAAG GAA ACACGUUC GAA AGACACGU GAA AGAGACAC GAA AGUCUUCU GAA AGGUGCCC GAA AUGUUCCU GAA AUAUGUUC GAA AUGUCUUJC GAA AGGAUGUC GAA AAGGAUGU GAA ACUUCUGU GAA AACUUCUG GAA AGAACUJLC GAA ACGAGAAC GAA AACGAGAA GAA AUCUCUAA GAA AAUCUCUA GAA AGCAGGUG

CGGACAGUI

GGACAGUUJ;

UGCACCAUP

ACCAUAGUP

CAUAGUAUC

CCACCACUC

CUCAAGAJUU

UCAAGAUUA

AGAUUACUC

UACUCCAUC

CCAUCACUC

CUGAACCUU

AACCUEJGUC

CUUGUCAUC

GAACGUGUC

ACGUGUCUC

GUGUCUCUA

AGAAGACUC

GGGCACCUA

AGGAACAUA

GAACAUAUA

GAAGACAUC

GACAUCCUUI

ACAUCCUUC

ACAGAAGUJ

CAGAAGUUC

GAAGUUCUC

GUtJCUCGUU UtJCUCGUUA

UUAGAGAUUJ

UAGAGAUUC

CACCUGCUU

JAACAACAG

SACAACAGA

LGUAUCAGC

LUCAGCAAG

AGCAAGCA

AAGAUuAc

ACUCCAUC

.CUCCAUCA

CAUCACUC

ACUCUGAA

UGAACCUU

GUCAUCAA

AUCAAGAA

AAGAACGU

UCUAGAAG

UAGAAGAC

GAAGACUC

GGGCACCU

UGCGUGCA

UACACAGG

CACAGGGG

CUUtCGGAA

CGGAAGAC

GGAAGACA

CUCGUUAG

UCGIJUAGA

GUITJAGAGA

AGAGAU-UC

GAGAUTUCG

CGGAAGCG

GGAAGCGC

CAAAACCU

164

C

2022 2030 2038 2045 2047 2051 2059 2061 2068 2069 2076 2082 2090 2100 2105 2109 2113 2114 2132 2150 2151 2153 2154 2155 2156 2179 2180 2181 2183 2192 2213 2215

GAGGUUL

UAGUCAC

AGACCUC

CUGAUGG

CACUGAU

GAG CCAC

AGGUCGU

UAAGGUC

GACAGUCI

UGACAGU(

UCUAGCMt

GACACCUC

GGCGCGG(

AGtJGAUCt

AACCAAGL

UUUGAACC

UGUUUUUG-

UUGUUUUU

UCULJGUUG

CCUAAAAU

UCCUAAAA

GGUCCUAA

UGGUCCUA

CUGGUCCU

CCUGGUCC

UUUCAAUA

CUUUCAAU

UCUUUCAA

ACUCtJUUC.

UCCUCUGU

CACCUAUA

GGCACCUA

[U CUGAUGA 'U CUGAUGA 'G CUGAUGA A CUGAUGA G CUGAUGA: U CUGAUGA A. CUGAUGA: 37 CUGAUGA: 'J CUGAUGA

CUGAUGA

J CUGAUGA) CUGAUGA CUGAUGA X JCUGAUGA X TCUGAUGA 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 X GA X GA X GA X GA X GA X GA K GA K GA.

C GAj ~GA2

GAI

GA;

GA;

GAP

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

AAAGCAGGU

AAGGUUUUG

AAGUCACUG

AACCUCGUA

AAGACCUCG

~AUGGAGAC

~AGCCACUG

~AGAGCCAC

~AGGUCGUA

~AAGGUCGU-

kACAGUCUA

AGCIJUGAC

ACACCUCU

AGGCGCGG

AUCUGAGG

AGUGAUCU

ACCAAGUG

AACCAAGU

AUUUUGUG

AUUCCCGG

AAUUCCCG

AUAAUUCC

AAUAAUUC

AAAUAAUU

AAAAUAAU

ACAGCGUG

AACAGCGU

AAACAGCG

AUAAACAG

ACUCUIJUC

ACACCCUc

AGACACCC

ACCUGCUUE

CAAAACCU

CAGUGACU

UACGAGGU

CGAGGUCU

GUCUCCAU

CAGUGGCU

GUGGCUCU

UACGACCUI

ACGACCUU)

UAGACUGUC

GUCAAGCU;

AGAGGUGUC

CCGCGCCUC

CCtJCAGAUC

AGAUCACUU

CACTJUGGUU

ACUTUGGtjUC

CACAAAAUA

CCGGGAAUU

CGGGAAUTUA

GGAAUUAUUr GAAUUAtUU

AAUUAUUUU

AUUALUUJUA

CACGCUGUU

ACGCUGUUU

CGCUGUTUUA

CUGUUUAUU

GAAAGAGUC

GAGGGUGTJC

GGGUGUCUA

IC AAAACCUC 'C AGUGACIJA A CGAGGUCU C UCCAUCAG C CAUCAGUG C AGUGGCUC

UACGACCU

k. CGACCUJA J AGACUGUC k~ GACUGUCA

AAGCUAGA

GAGGUGUC

CCCGCGCC

AGAUCACU

ACUTUGGLU

GGUUCAAA

CAAA.AACA

AAAAACAA

CAACAAGA

AUUtJUAGG

UUUUAGGA

UUTAGGACC

UAGGACCA

AGGACCAG

GGACCAGG

UAUUGAAA

AtJUGAAAG

UUGAAAGA

GAAAGAGU

ACAGAGGA

UAUAGGUG

2217 UCGGCACC CUGAUGA X GAA AUAGACAC GUGUCUAUA GGUGCCGA 165 2263 2267 2284 2293 2309 2315 2342 2344 2345 2346 2351 2354 2355 2357 15 2361 2363 2365 2366 2369 2386 2388 2389 2391 2392 2399 2410 2416 2420 2423 2424 2441 2442 2473

CGGUGAG(

UGCACGGI

ACUUGUC.

CCAGGUT..

GUGAGCGI

GUGCACGL

AGCCAAAP

GGAGCCA.P

AGGAGCCA

AAGGAGCC

GUUAGAAG

AGAGLUAG

GAGAGUUA

AAGAGAGU

GAUGAAGA

CUGAUGAA

UTUCUGAUG

LTUICtGAU

AGUUUUCU

CGGAAGAA

TJUCGGAAG

CUUCGGAA

UACUUCGG

UUACUTUCG

UCUGUCUU

tJUGACAGG

UAAUGAUEJ

UCCAUAAU

GGGUCCAU

UGGGUCCA

UCCAGGGG

AUCCAGGG

UGGCAUCA

37 CUGAUGA J CUGAUGA

JCUGAUGA

7CUGAUGA

ICUGAUGA

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 I CUGAUGA2 CUGAUGA2

CUGAUGA)

CUGAtJGA C GAA AGGCUGCG IGAA AGGUAGGC GAA AGGUUCCU GAA ACUUGUCU GAA AUCAGCUC *GAA AGCGUGAU *GAA AGGGUCGC GAA AGAGGGUC GAA AAGAGGGU GAA AAAGAGGG GAA AGCCAAAA GAA AGGAGCCA GAA AAGGAGCC GAA AGAAGGAG GAA AGUUAGAA GAA AGAGUUEAG GAA AGAGAGUU GAA AAGAGAGU GAA AUGAAGAG GAA ACCGCUUC GAA AGACCGCU GAA AAGACCGC GAA AGAAGACC GAA AAGAAGAC GAA ACUUCGGA GAA AGUCUGUC GAA ACAGGUAG GAA AUUGACAG GAA AUGAUTUGA GAA AAUGAUUG GAA ACUtJCAUC GAA AACUUCAU GAA AGGGCAGC

CGCAGCCU)

GCCUACCUC

AGGAACCUC

AGACAAGUC

GAG CUGAUC

AUCACGCUC

GCGACCCUC

GACCCUCUJ

ACCCUCUU

CCCUCUuu

UUUUGGCUC

UGdCUCCUU GGCUCCUjC CUCCUUtCUA

UUCUAACUC

CUAACUCUC

AACUCUCUUI

ACUCUCUUC

CUCUUCAUC

GAAGCGGUC

AGCGGUCUU

GCGGUCUUC

GGUCUUCUU

GUCtJUCUUC

UCCGAAGUA

OACAGACUA

CUACCUGUC

CUGUCAAUC

UCAAUCAUJ

CAAUCAUUA

GAUGAAGUU

AUGAAGUUIC

GCUGCCCUA

k. CCUCACCG

ACCGUGCA

AGACAAGU

AAACCUGG

ACGCUCAC

ACGUGCAC

UUUUGGCU

UUGGCUCC

UGGCUCCU

GGCUCCUU

CUTJCUAAC

CUAACUCU

UAACUCUC

ACUCUCUt)

UCUUFCAUC

UUCAUCAG

CAUCAGAA

AUCAGAAA

AGAAAACU

UUCUUCCG

CUUCCGAA

UUCCGAAG

CCGAAGUA

CGAAGUAA

AAGACAGA

CCUGUCAA

AAUCAUTUA

AUUAUGGA

AUGGACCC

UGGACCCA

CCC CUGGA

CCCUGGAU

UGAUGCCA

166 2494 CCCGUGCA CUGAUGA X GAA ACUCCCAC GUGGGAGtJU 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

UCCCGUG

GAUUUG C UUCCGAGi

CCUCUUC(

UUUCCC.Aj CULUCCC2

ACUTUUCC(

GCUtJGAAC

GAGGCLTIC

AGAGGCI.

CAAAUGC;

UAAUGCCP.

UUAAUGCC

GAUUUCUU

UGAUUUCU

AGGUGGGU

CCUCUUUC

GAG CUUtJG

GGUCAUCA

AAGAUCUU

UGGGUCAA

UGUGGGUC

UGAUGGcc

AUUCAGAU

CACAUUCA

AGGAGGUU

CAGGAGGU

GCUCCCAG

CACCAUCA

UAUTUCCAC

AUUUGCAG

C CUGAUGA C CUGAUGA

CCUGAUGA

CUGAUGA

~CUGAUGA

~CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

JCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA)

CUGAUGA

CUGAUGA

CUGAUGA 2 CUGAUGA 2 CUGAUGA Y CUGAUGA Y CUGAUGA X X GAA AACUCCCA X GAA AGUUUCAG K GAA AUUUGCCU K GAA AGCGAUUJ K GAA AGCCCCUC GAA AAGCCCCU C GAA AAAGCCCC CGAA ACUUUCCC [GAA ACGACUUU :GAA AACGACUU GAA AGGCUUGA GAA AUG CAGAG GAA AAUGCAGA GAA AUG CCAAA GAA AAUGCCAA GAA AUUUCUUA GAA ACAUCUJC GAA ACUCACUG GAA AGCUUUGU GAA AGUUCGGU GAA AUCUUGAG GAA AGAUCUUG GAA AUGUGGGU GAA AUGGCCGA GAA AUGAUGGC GAA ACCACAUU GAA AACCACAU GAA AGGUtJAAC GAA AGGCCCUC GAA AUCACCAU GAA AUUCCACG

UGGGAGUY

CUGAAACU

AGGCAAAU

AAAUCGCU(

GAGGGGCU1

AGGGGCULTI

GGGGCUUUL

GGGAAAGUC

AAAGUCGUL

AAGUCGUUC

UCAAGCCUC

CUCUGCAUU

UCUGCAUUU

UULUGGCAU'U

UUGGCAUUA

UAAGAAAUC

GAAGAUGUU

CAGUGAGUA

ACAAAGCUC

ACCGAACUC

CUCAAGAUC

CAAGAUCUU

ACCCACAUC

UCGGCCAUC

GjCCAUCAUC

AAUGUGGUU

AUGUGGUUA

GtJUAACCUC

GAGGGCCUC

AUGGUGAUjC

CGUGGAAUA

UGCACGGGA

k. GGCAAAUC

:GCUCGGAA

-GG.AAGAGG

JUUGGGAAA

J UGGGAAAG J GGGAAAGU IGUtJCAAGC J CAAGCCUC

AAGCCUCU

UGCAULUUG

rUGGCAUUA

GGCALTUAA

AAGAAAUC

AGAAAUCA

ACCCACCU

GAAAGAGG

CAAAGCUC

UGAUGACC

AAGAUCUU

UUGACCCA

GACCCACA

GGCCAUCA

AUCUGAAU

UGAAUGUG

AACCTJCCU

ACCUCCUG

CUGGGAGC

UGAUGGUG

GUGGAAUA

CUGCAAAU

2770 GGUUUCCG CUGAUGA X GAA AUUUGCAG CUGCAAAUA CGGAAACC 167 2782 GGUAGUUG CUGAUGA X GAA ACAGGUUU AAACCUGUC CAACUACC 2788 2792 2809 2810 2812 2813 2817 2819 10 2836 2841 2849 2900 2909 15 2917 2924 2938 2939 2982 2983 2993 2995 3008 3026 3027 3028 3031 3036 3037 3038 3061 3062

UCUUGAGC

ULJGCUCL

GACAGAAL

AGACAGA)

UGAGACAC

UUGAGACP

CUUGUEFJG.A

UCCUUGUU

CCAUAUGC

GAGCUCCA

UCUUUCUU

ACACUGUC

GAG CUG CU UGACACtU

GAGCUGGU

GGAAGCUG

CUUCAGGG

UCU.UCAGG

CUCACUGU

UCUCACUG

UGCUUGGA

GCUGCUUG

UCCAUGGU

CUGUAGGA

ACUGUAGG

AACUGUAG

GGAAACUG

CACUUGGA

CCACUUGG

GCCACUUG

AGGACAGA

'CUGAUGA

JCUGAUGA

JCUGAUGA

CUGAUGA

CUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA2 CUGAUGA2 CUGAUGA2

CUGAUGA)

CUGAUGA

CUGAUGA)

GA;

GA;

GA;

GA;

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

\AGtJUGGAC

SAGGUAGUU

AGUCACGU

AAGUCACG

AUAAGUCA

AAUAAGUC

ACAGAAUA

AGACAGAA

AGGCUGCG

AUGCAAGG

AGCUCCAU

AGGCGGGG

ACACUGUC

AGCUGCUG

ACACUUGA

AGCUGGUG

AGCUGGAG

AAGCUGGA

AUCCUCGU

AAIJCCUCG

AUCUCACU

AGAUCUCA

AGGGGCUG

AUCAGGUC

AAUCAGGU

AAAUCAGG

AGGAAAUC

ACUGUAGG

AACUGUAG

AAACUGUA

ACUCCAUG

GUCCAACUj

AACUACCU(

ACGUGACUT

CGUGACU2

UGACUUAUTL

GACUUAUTUC

UAUUCUGUC

UIJCUGUCUC

CGCAGCCUL

CCUTUGCAU.A

AUGGAGCUC

CCCCGCCUA

GACAGUGUC

CAGCAGCUC

UCAAGUGUC

CACCAGCUC

CUCCAGCUJI

UCCAGCUUC

ACGAGGAUU

CGAGGAUUA

AGUGAGAUC

UGAGAUCUC

CAGCCCCUC

GACCUGAUU

ACCUGAUU

CCUGAUJUC

GAUTJUCCUA

CCUACAGU

CUACAGUU

UACAGUUUC

CAUGGAGUU

~CCUCAAGA

:AAGAGCAA

J AUUCUGUC k UUCUGUCU

JCUGUCUCA

UGUCUCAA

UCAACAAG

AACAAGGA

FGCAtJAUGG

UGGAGCUC

JAAG.A6AAGA

GACAGUGU

AGCAGCUC

AAGUGUCA

ACCAGCUC

CAGCUTUCC

CCCUGAAG

CCUGAAGA

ACAGUGAG

CAGUGAGA

UCCAAGCA

CAAGCAGC

ACCAUGGA

UCCUACAG

CCUACAGU

CUACAGUU

CAGUTUUCC

UCCAAGUG

CCAAGUGG

CAAGUGGC

UCUGUCCU

GAGGACAG CUGAUGA X GAA AACUCCAU AUGGAGUUU CUGUCCUC 168 3063 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

GGAGGAC

UUCUGGA

ACUTUUCU

UCCCGAU

GTJCCCGA1

CAGGUCC(

GAUAAAA(

UCAGAUA)

CUCAGAUJ

UCUCAGAt.

UUCUCAGI

UGUUCUCU

AAGUCGCP

AAAGUCGC

CCAGGCCA

CCCAGGC C CtJUAUAAA

UUCLTUAUA

GUUCUTUAU

GGUUCUUA

AGGGUUCU

CCUCACAU

UCCUCACA

AAGUCGAG

GGGAAGUC

UUtJAGGGG

UUUUAGGG

AUCCATtU

GGALUUCAG

CAAAGAUG

UUGUCAAA~

CCUUGUCA

ACCLTUGUC

A CUGAUGA G CUGAUGA 3 CUGAUGA

CUGAUGA

J3 CUGAUGA

CUGAUGA

SCUGAUGA

k. CUGAUGA

~CUGAUGA

J CUGAUGA iCUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA Y 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 X GA X GA X GK.

X GA)~ X GA) X GA2 K GA7 K GA;

GA;

C GAP~

CGAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

~AAACUCCA

~ACAGAAAC

~AGGACAGA

SAUGCACUtJ ~AAuGCACU

'AUGAAUGC

SAUGUUUCU

SAGGAUGUU.

SAAGGAUGU

AAAGGAUG

AAAAGGAU

AUAAAAGG

AUCUTUCAC

AAUCUUCA

AGUCGCAA

AAGUCGCA

AUCCCGGG

AUAUCCCG

AAUAUCCC

AAAUAUCC

AUAAAUAU

AUCAGGGU

AAUCAGGG

AUCUCCUC

AGUAUCUC

AGUCGAGU

AAGUCGAG

AGGGGAAG

AGCCAUCC

AUUCAGGA

AUGGAUUC

AGAUGGAU

AAGAUGGA

UGGAGUUU

GUtJUCUGU

UCUGUCCU

AAGUGCAU

AGUGCAUU(

GCAUUCAUC

AGAAACAU(

AACAUCCUJI

ACAUCCU~n CAUCCUUMt AUCCtUUU CCUUtJUAUC

GUGAAGAU.

UGAAGAUUU

UUGCGACUU

UGCGACLUU

CCCGGGAUA

CGGGAUAUU

GGGAIJALUU

GGAUALTUtUA

AUAUUUAUA

ACCCUGAUU

CCCUGAUUTA

GAGGAGAUA

GAGAUACUC

ACUCGACUU

CUCGACUuc

CUUCCCCUA

GGAUGGCuc

UCCUGAAUC

GAAUCCAUC

AUCCAUCUU

UCCAUCULJU

C UGUCCUCC C CUCCAGAA C CAGAAAGU J3 CAUCGGGA

SAUCGGGAC

GGGACCUG

:CUUIJUAUC

JUUAUCUGA

J UAUCUGAG

IAUCUGAGA

UCUGAGAA

UGAGAACA

UGCGACUU

GCGACUUU

UGGCCUGG

GGCCUGGC

UUUAUAAG

UAUAAGAA

AUAAGAAC

UAAGAACC

AGAACCCU

AUGUGAGG

UGUGAGGA

CUCGACUU

GACUUCCC

CCCCUAAA-

CCCUAAAA

AAAUGGAU

CUGAAUCC

CAUCUUUG

UUUGACAA

UGACAAGG

GACAAGGU

169 0 .00 0 0 0 0 3251 3253 3277 3280 3289 3302 3304 3305 3307 3310 3311 3318 3319 3321 3325 3352 3353 3397 341.3 20 3415 3422 3427 3432 3466 3467 3476 3488 3500 3501 3512 3531 3532 3536

GUGCUGU

UGGUGCU(

CGCCAUA(

ACACGCCj

CCCACAG(

AAGGAGAI

CUAAGGAC

CCUAAGGI

CCCCUAAC

AACCCCCL

GAACCCCC

GUAUGGAG

GGUAUGGA

UGGGUAUG

CUCCUGGG

GGCUGCAG

CGGCUGCA

GUGUGGCA

AUUUGGUA

UGALITJUGG

UCCAACAU

AGCAAUCC

GUGCCAGC

GUUCAGCA

AGUUCAGC

UUCUCCAC

AGGUCACC

UUGGCUUG

GUUGGCUU

UCCUGtJUG

GGGGAUGU

GGGGGAUG

UUGAGGGG

k CUGAUGA

CUGAUGA

3 CUGAUGA k CUGAUGA

CUGAUGA

k CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

I CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA Y X GAA ACCUUGUC K GAA AGACCUUG K GAA ACCACACA K GAA AGGACCAC K GAA ACACGCCA C GAA AUCUCCCA C GAA AGAUCUCC C GAA AAGAUCUC I GAA AGAAGAUC GAA AGGAGAAG GAA AAGGAGAA GAA ACCCCCUA GAA AACCCCCU GAA AGAACCCC GAA AUGGAGAA GAA AGUCUUCA GAA AAGUCUUC GAA ACUCCGGG GAA AUUUCAGG GAA AGAUUUCA GAA AUUUGGUA GAA ACAUGAUU GAA AUCCAACA GAA ACCGGGGC GAA AACCGGGG GAA AGUUCAGC GAA AGULTUCUC GAA AGCAGGUC GAA AAGCAGGU GAA ACGUUGGC GAA AUCUUUCC GAA AAUCUUUC GAA AUGUAAUC

GACAAGGU

CAAGGUCU.

UGUGUGGU

GUGGUCCU,

UGGCGUGLTI

UGGGAGAU(

GGAGAUCUT

GAGAUCUU(

GAUCUUCU(

CUUCUCCUT

uucuccuu;

UAGGGGGUL

AGGGGGUUC

GGGGUUCUC

UUCUCCAUA

UGAAGACUU

GAAGACULJC

CCCGGAGUA

CCUGAAAUC

UGAAAUCUA

UACCAAAUC

AAUCAUGUU

UGUUGGAUTJ

GCCCCGGUU

CCCCGGUUU

GCUGAACUU

GAGAAACUU

GACCUGCUU

ACCUGCUUC

GCCAACGUC

GGAAAGAUU

GAAAGAUUA

GAUUACAUC

C UACAGCAC A CAGCACCA C CUAUGGCG k UGGCGUGU J GCUGUGGG 7 UUCUCCLTEJ J CUCCUUAG

UCCUUAGG

LWAGI

J AGGGGGUU

GGGGGUUC

T CUCCAUAC

UCCAUACC

CAUACCCA

CCCAGGAG

CUGCAGCC

UGCAGCCG

UGCCACAC

UACCAAAU

CCAAAUCA

AUGUUGGA

GGAUUGCU

GCUGGCAC

UGCUGAAC

GCUGAACU

GUGGAGAA

GGUGACCU

CAAGCCAA

AAGCCAAC

CAACAGGA

ACAUCCCC

CAUCCCCC

CCCCUCAA

170 3542 AUGGCAUU CUGAUGA X GAA AGGGGGAU AUCCCCCUC AAUGCCAU 4@@e 4~ V Se S S 3551 3558 3567 3571 3572 3577 3580 3592 10 3593 3595 3605 3606 3607 3608 3619 3620 3627 3633 3634 3635 3636 3639 3640 3649 3664 3668 3675 3676 3677 3682 3683

CUAGUCA

ACUGULUI

UGUGAAGi

AGUAUGU(

GAGUAUGI

GGGUCGA(

UGGGGGUC

CCTJCAGAC

UCCUCAGI

GGUCCUCP

UCCUUJGAP

GUCCUUGA

CGUCCUUG

CCGUCCUU

GAUCUGCA

GGAUCUGC

AAAAUGUG

GGAAUGAA

CGGAAUGA

CCGGAAUG

UCCGGAAU

GCUUCCGG

AGCLUCCG

CAUCAUCA

CGULUJACA

AAAGCGLU

GAAUUtJGA

UGAAUTJUG

AUGAAUtU GGCtJCAUG

AGGCUCAU

GCUGAUGA

C CUGAUGA

:CUGAUGA

3 CUGAUGA J CUGAUGA 3CUGAUGA

CUGAUGA

;CUGAUGA

CUGAUGA

CUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA

CUGAUGA)

CUGAUGA

CUGAUGA Y CUGAUGA Y CUGAUGA N CUGAUGA X CUGAUGA X X GAA AUGGCAUJ! X GAA AGUCAGUA K GAA ACUGUULJC K GAA AGCUACUG K GAA AAGCUACU GAA AUGUGAAG C GAA AGUAUGUG C GAA AGGUGGGG [GAA AAGGUGGG GAA AGAAGGUG GAA AGGUCCUC GAA AAGGUCCU GAA AAAGGUCC GAA AAAAGGUC GAA AGCCGUCC GAA AAGCCGUC GAA AUCUGCAA GAA AUGUGGAU GAA AAUGUGGA GAA AAAUGUGG GAA AAAAUGUG GAA AUGAAAAU GAA AAUGAAAA GAA AGCUUCCG GAA AUCUCACA GAA ACAUAUCU GAA AGCGUUUJA GAA AAGCGUUU GAA AAAGCGUU GAA AUUUGAAA GAA AAUJUGAA

AAUGCCAU

UACUGACU

GAAACAGU

CAGUAGCU

AGUAGCUU,

CUUCACAU,

CACAUACU(

CCCCACCUI

CCCACCUTU(

CACCUUtCUC

GAGGACCUL

AGGACCUUI

GGACCUUL

GACCUUUUC

GGACGGCUL

GACGGCUUUT

UUGCAGAUC

AUCCACAUUJ

UCCACAUU

CCACAUULU

CACAUtJUUC

AUUUUCAUU

UIUUCAUUC

CGGAAGCUC

UGUGAGAUA

AGAUAUGUA

UAAACGCUUJ

AAACGCUUJ

AACGCLTJJC

UTUUCAAAUU

UUCAAAUUC

A CUGACUAG A GAAACAGU A GCUUCACA UI CACAUACU C ACAUACUC k. CUCGACCC

GACCCCCA

J CUCUGAGG

UCUGAGGA

:UGAGGACC

JUUCAAGGA

J UCAAGGAC

JCAAGGACG

~AGAGG

UGCAGAUC

GCAGAUCC

CACAUUUU

UTJCAtJUCC

UCALTUCCG

CAUtJCCGG

AUUCCGGA

CCGGAAGC

CGGAAGCU

UGAUGAUG

UGUAAACG

AACGCUUtJ

UCAAAUJTC

CAAAUTUCA

AAAUUCAU

CAUGAGCC

AUGAGCCU

3701 AAGGUUUU CUGAUGA X GAA AUUICUUUC GAAAGAAUC AAAAccUU 171 3709 GCUCCUCA CUGAUGA X GAA AGGUtJUUG CAAAACCUU UGAGGAGC 3710 3719 372.0 3721 3730 3736 3742 3743 3751 3753 3765 3771 3781 15 3787 3799 3800 3829 3839 20 3844 3851 3858 3878 3879 3880 3885 3901 3902 3907 3908 3910 3926

AGCUCCU(

UUCtGGUG)

GUUCGGUC

AGUTUCGGT.

UGGAGGUC

CAAACAUC

AGUCCUCP

UAGUCCUC

CCAGCUGP

GUC CAG Ct

CAGAGUGC

GCCCAGCA

GCAAGGGG

GCUUCAGC

UCCAGGUG

GUCCAGGU

UCUTUCAUG

CUCAAGUC

CUAUTUCUC

UUACUCGC

CUUGCUU

AGAUCGGA

CAGAUCGG

GCAGAUCG

CCUCGGCA

AGAAGCAG

GAGAAGCA

AGCUGGAG

CAGCUGGA

CACAGCUG

ACGGGCCU

-CUGAUGA

k~ CUGAUGA

CUGAUGA

JCUGAUGA

;CUGAUGA

;CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I

CUGAUGA

CUGAUGA2

CUGAUGA

CUGAUGA)

C GAA AAGGUUUU C GAA AGCUCCUC I GAA AAGCUCCU CGAA AAAGCUCC GAA AGUUCGGU GAA AGGUGGAG GAA ACAUGGAG GAA AACAUGGA GAA AGUCCUCA GAA AUAGUCCU GAA AGUGUCCA GAA AGUGCUAG GAA AGCCCAGC GAA AGGGGGAG GAA ACCGCUUC GAA AACCGCUU GAA AGGCCUUJG GAA AUCUUCAU GAA AGUCUAUC GAA AUIJCUCAA GAA ACUCGCUA GAA AGUCCCGC GAA AAGUCCCG GAA AAAGUCCC GAA AUCGGAAA GAA AGCUGGGC GAA AAGCUGGG GAA AGCAGAAG GAA AAGCAGAA GAA AGAAGCAG GAA AUGUGGCC

AAAACCU

GAGGAGCTP

AGGAGCUUI

GGAGCUUU(

ACCGAACUC

CUCCACCU(

CUCCAUGU.

UCCAUGJUL

UGAGGACU;

AGGACUAUC

UGGACACUP

CUAGCACUC

GCUGGGCUC

CUCCCCCtUu

GAAGCGGUU

AAGCGGUUC

CAAGGCCUC

AUGAAGAUA

GAUAGACUU

UTUGAGAAUA

UAGCGAGUA

GCGGGACUU

CGGGACUUU

GGGACUUUC

TUUCCGAUC

GCCCAGCUJ

CCCAGCUTUC

CUUCUGCUU

UUCUGCUUC

CUGCUIJCUC

GGCCACAUC

LU GAGGAGCU J UCACCGAA J CACCGAAC

ACCGAACU

:CACCUCCA

:CAUGUUUG

JUGAGGACU

IGAGGACUA

UCAGCUGG

AGCUGGAC

GCACUCUG

UGCUGGGC

CCCCUUGC

GCUGAAGC

CACCUGGA

ACCUGGAC

CAUGAAGA

GACUUGAG

GAGAAUAG

GCGAGUAA

AAAGCAAG

UCCGAUCU

CCGAUCUG

CGAUCUGC

UGCCGAGG

CUGCUTUCU

UGCtJUCUC

CUCCAGCU

UCCAGCUG

CAGCUGUG

AGGCCCGU

3949 CCAGCUCA CUGAUGA X GAA AUUCAUCG CGAUGAAUC UGAGCUGG 172 3967 AACAGCAG CUGAUGA X GAA ACUCCUUU AAAGGAGUC CUGCUGUU a 3975 3976 3978 3991 3997 4006 4009 4012 4015 4027 4033 4034 4036 4066 4068 4069 4071 4075 20 4077 4083 4084 4085 4091 4093 4094 4099 4117 4118 4119 4120 4128

GGGUGGA

GGGGUGG

UGGGGGU,

CGGAGUU

ACACCAC(

AGGAGUAC

GGGAGGA(

GCGGGGA(

CGGGCGGC

AGAAG CUT

CUGGUGAC

GCUGGUG~z

GGGCUGG.

AUGUAUAA

AGAUGUAUJ

UAGAUGUA

CAUAGAUG

AACUCAUA

UAA.ACUCA

UAGGUGUA

AUAGGUGU

AAUAGGUG

GAGCGGAA

UGGAGCGG

GUGGAGCG

CUCCUGUG

GUCACGAA

GGUCACGA

AGGtUCACG

AAGGUCAC

CACGAUUA

G CUGAUGA A CUGAUGA 3 CUGAUGA 3CUGAUGA 3CUGAUGA

ZCUGAUGA

3 CUGAUGA 7CUGAUGA

.CUGAUGA

JCUGAUGA

CUGAUGA

CUGAUGA

rCUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGAI

CUGAUGA I

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA Y CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X X GA K GA K GA K GA K GA C GAj c GA-2

GP)

GA;

GA)

GPO

GAP~

GAP~

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

AACAGCAGG

AAACAGCAG

AAGAACAGC

AAGUCUGGG

AAGUTUGUAG

AACACCACG

~ACAACACC

'AGUACAAC

SAGGAGUAC

~.AGGCGGGC

AGCULJUAG

AAGCTJUUA

AGAAGCUUJ

ACUGUCAG

AtJACUGUC

AAUACUGU

AUAAUACU

AUGUAUAA

AGAUGUAU

ACUCAUAG

AACUCAUA

AAACUCAU

AGGUGUAA

AUAGGUGU

AAUAGGUG

AGCGGAAU

AGCAGCUG

AAGCAGCU

AAAGCAGC

AAAAGCAG

AGGUCACG

CCUGCUGU

CUGCUGUU

GCUGUUJCU

CCCAGACU

CUACAACUi CGUGGUGU1I GGUGUUGU2

GUUGUACU(

GUACUCCUC

GCC CC CUI CUAAAG CUT.

UAAAGCUUC

AAGCUUTCUC

CUGACAGUA

GACAGUAUU

ACAGUAUUA

AGUALTUAUA

UUAUACAUC

AUACAUCUA

CUAUGAGUUJ

UAUGAGLUU

AUGAGLUJUA

UUACACCUA

ACACCUALU

CACCUAUUC

AUUCCGCUC

CAGCUGCUU

AGCUGCUUU

GCUGCUUU

CUGCUJUUUC

CGUGACCtU U CUCCACCC C UCCACCCC C CACCCCCA A, CAACUCCG

SCGUGGUGU

J GUACUCCU k CUCCUCCC

SCUCCCCGC

CCCGCCCG

AAGCUUCU

JCUCACCAG

UCACCAGC

ACCAGCCC

UUAUACAU

AUACAUCU

UACAUCUA

CAUCUAUG

UAUGAGUUI

UGAGUUUEA

UACACCUA

ACACCUAU

CACCUAUUL

UTUCCGCUC

CCGCUCCA

CGCUCCAC

CACAGGAG

UUTCGUGAC

UCGUGACC

CGUGACCU

GUGACCUU

UAAUCGUG

4129 GCACGAUU CUGAUGA X GAA AAGGUCAC GUGACCUUU AAUCGUGC 173

S

S. S

S

SS.

4130 4133 4139 4140 4141 4142 4143 4146 4147 4148 4149 4150 4153 4154 -4155 4158 4159 4162 4165 20 4171 4172 4173 4178 4189 4198 4199 4216 4219 4221 4224 4225 4233 4249 AGCACGA2

AAAAGCAC

AAACAAAA

AAAACAAA

AAAAACAA

AAAAAACA

CAAAAAAC

AAACAAAA

AAAACAAA

CAAAACAA

ACAAAACA

AACAAAAC

ACAAACAA

AACAAACA

CAACAAAC

CAACAACA

GCAACAAC

ACAGCAAC

AAAACAGC

UUAGUCAA

GUTUAGUCA

UGUUAGUC

AUTUCUUGU

ACUGGGGU

ACGUCACU

CACGUCAC

AACAAUAG

UCUAACAA

UCUCUAAC

'AUUUCUCU

GAUTUUCUC

GCGGGGGG

GUEJACCCU

ICUGAtJGA

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

GAIA

GATA

GAA

AAAGGUCA

ALTUtAAAGG

AGCACGAU

AAGCACGA

AAAGCACG

AAAAGCAC

AAAAAGCA

ACAAAAAA

AACAAAAA

AAACAAAA

AAAACAAA

AAAAACAA

ACAAAAAA

AACAAAAA

AAACAAAA

ACAAAACA

AACAAAAC

ACAAACAA

ACAACAAA

ACAGCAAC

AACAGCAA

AAACAGCA

AGUCAAAA

ACAUUCUU

ACUGGGGU

AACUGGGG

AUTUCUUCA

AGUAUUCU

AUAGUALU

ACAAUAGU

AACAAUAG

AUUTUCUCU

AGGCUUUG

UGACCULUA

CCUtJUAAUC

AUCGUGCUU

UCGUGCUUU

CGUGCUUUEJ

GUGCLUUUU

UGCLUUUUU

UUUUUJGULrJ

UUUUUGUUU

UUUUGUUTU

UUUGULTTU

UUGLUUUUU

UUUUUTUGUU

UUUUJUGUUU

UUUUGUULU

UGUUUUGUU

GUUUUGUU

UUGUUUGUU

UTUUGUTUGUUI

GUUGCUGULJ

UUGCUGUUU

UGCUGUUUU

UUUUGACUA

AAGAAUGUA

ACCCCAGUU

CCCCAGUtJA

UGAAGAAUA

AGAAUACUA

AAUACUALU

ACUAUUGUU

CUAUUGUUA

AGAGAAAUC

CAAAGCCUC

AUCGUGCU

GUGCUUUU

UIUUGUUtJ

UUGUU'U

UUGUULUU

UGLUUUUU

GUULTUULUG

IJUUUGUU

UUTUGUUUU

UUTGUUUTUG

UGUUTUUGU

GUUUUGUUT

UULGUUUGU

UGUtJUGUUJ

GUTUUGUU.G

UGUUGUUG

GUUTGUTUGC

GUUGCUGU

GCUGUUUU

UUGACUAA

UGACUAAC

GACUAACA

ACAAGAAU

ACCCCAGU

AGUGACGU

GUGACGUG

CUAUUGUUJ

UUGUUAGA

GUTUAGAGA

AGAGAAAU

GAGAAAUC

CCCCCCGC

AGGGUAAC

174

S

4255 4282 432i 4341 4350 4358 4359 4363 4387 4391 4393 4395 4397 4398 4445 4446 4456 4460 4487 4492 4500 4501 4509 4510 4512 4516 4524 4531 4532 4533 4543 4544 4553 GtJCCAGGI

GGUCGCCJ

GCUGCAG(

ACUGCCU(

AAUGGGCT

CAUGAGCT

CCAUGAGC

GCAGCCAI

GAGAGAC?

AUAAGAG;

CCAUAAGP

CUCCAUAA

UCCUCCAIU

UTJCCUCCA

GCAUCCCA

CGCAUCCC

ACAGGACG

CUCCACAG

GCAUAGCG

AAGUGGCA

AGUCACUG

AAGUCACU

GGAGUGAG

AGGAGUGA

CCAGGAGU

GAGGCCAG

AAACAGCG

GGGCCCGA

GGGGCCCG

'GGGGGCCC

CCUCUUTGG

ACCUCUUG

UGCUCUGA

LCUGAUGA

k. CUGAUGA 3 CUGAUGA

-CUGAUGA

J CUGAUGA J CUGAUGA

-CUGAUGA

JCUGAUGA

LCUGAUGA

LCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

*CUGAUGA

*CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA2

CUGAUGA

CUGAUGA)

CUGAUGA 2 CUGAUGA 2 CUGAUGA Y~ CUGAUGA Y K GA) K GA) C GAT? C GAP C GAP I GAIA

CGAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAJ

GAI

'ACCCUGAG

~AGGCACCU

SAGG4GUGGG

SAGUCCCAC

ACUGCCUC

AUGGGCUU

AAUGGGCU

AGCUAAUG

AGCAGGUC

ACAGAGCA

AGACAGAG

AGAGACAG

AGAGAGAC

AAGAGAGA

AGCCUUUU

AAGCCUU

ACGCAUCC

ACGGACGC

AG CCCC CU

AGCGGAGC

AGUGGCAU

AAGUGGCA

AGUCACUG

AAGUCACU

AGAAGUCA

AGUGAGAA

AGGCCAGG

ACAGCGGA

AACAGCGG

AAACAGCG

AGGG4GGCC

AAGGGGGC

ACCLTCUUG

CUCAGGGU

AGGUGCCU(

CCCACCCU(

GUGGGACUI

GAGGCAGUI

AAGCCCAUL

AGCCCAUU?

CAUUAGCUC

GACCUGCUC

UGCUCUGUC

CUCUGUCUC

CUGUCUCUC

GUCUCUCUU

UCUCUCUtJA

AAAAGGCUU

AAAGGCUUU

GGAUGCGUC

GCGUCCGUC

AGGGGGCUC

GCUCCGCUA

AUGCCACUU

UGCCACUUC

CAGUGACUU

AGUGACUTUC

UGACtJUCUC

UUCUCACUC

CCUGGCCUC

UCCGCUGUU

CCGCUGUUU

CGCUGUUUC

GGCCCCCUU

GCCCCCUUC

CAAGAGGUA

~ACCUGGAC

UGGCGACC

CCUGCAGC

k. GAGGCAGU

SAGCCCAUU

J AGCUCAUG

LGCUCAUGG

AUGGCUGC

UGUCUCUC

UCUCLUJAU

UCUUAUGG

LUAUGGAG

AUGGAGGA

UGGAGGAA

UGGGAUGC

GGGAUGCG

CGUCCUGU

CUGUGGAG

CGCUAUGC

UGCCACUU

CAGUGACU

AGUGACUU

CUCACUCC

UCACUCCU

ACUCCUGG

CUGGCCUC

CGCUGLUU

UCGGGCCC

CGGGCCCC

GGGCCCCC

CCAAGAGG

CAAGAGGU

UCAGAGCA

175 4555 UCTJGCUCU CUGAUGA X GAA AUACCUCU AGAGGUAUC AGAGCAGA

C

4577 4578 4579 4582 4598 4599 4601 4614 4615 4618 4620 4621 4625 15 4627 4628 4629 4630 4639 4641 4642 4646 4649 4653 4654 4655 4660 4669 4671 4672 4673 4682

GUCUAGGA

GGUCUAGG

UGGUCUAG

CCCUGGUC

UUCCCGAG

GUUCCCGA

UGGUUCCC

UUAAGALU

UUUAAGAU

AGAUTUUAA

AAAGALUU

AAAAGAUJ

CGGGAAAA

CCCGGGAA

UCCCGGGA

CUCCCGGG

ACUCCCGG

CAACAGAA

GACAACAG

AGACAACA

AAACAGAC

GGUAAACA

GGAUGGUA

UGGAUGGU

UUGGAUGG

AUGCLTUTUG

AUGUTUAAA

ACAUGUTUA

CACAUGU

ACACAUGU

CCCCCACU

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 I GAA ACGUCCCU GAA AACGUCCC GAA AAACGUCC GAA AGGAAACG GAA ACAUGUGC GAA AACAUGUG GAA AGAACAUG GAA ACUGUGGU GAA AACUGUGG GAA ALTUAACUG GAA AGAUUAAC GAA AAGAUUAA GAA AUUUAAGA GAA AGAUUUAA GAA AAGAUUUA GAA AAAGAtUU GAA AAAAGAUU GAA ACUCCCGG GAA AGACUCCC GAA AAGACUCC GAA ACAGAAGA GAA ACAACAGA GAA ACAGACAA GAA AACAGACA GAA AAACAGAC GAA AUGGUAAA GAA AUGCUUUG GAA AUAUGCUU GAA AAUAUGCU GAA AAAUAUGC GAA ACACAUGU

AGGGACGUL

GGGACGUUt.

GGACGUUUC

CGUUTUCCU;

GCACAUGL

CACAUGUUC

CAUGUTUCUC

ACCACAGUJ

CCACAGUU.A

CAGUUAAUC

GULJAAUCUU

UUAAUCtJUA UCUtJAAAUC

UUAA.AUCUU

UAAAUCUUU

AAAUCULUU

AAUCUUUUC

CCGGGAGUC

GGGAGUCUU

GGAGUCUUC

UCUUCUGUU

UCUGUUGUC

UUtGUCUGUU

UGUCUGUUU

GUCUGLTUUA

UUEJACCAUC

CAAAGCAUA

AAGCAUAUU

AGCAUAUUU

GCAUAUTUUA

ACAUGUGUC

JUCCUAGAC

JCCUAGACC

CUAGACCA

GACCAGGG

J CUCGGGAA

UCGGGAAC

GGGAACCA

rAAUCUTUAA

AUCUTUAAA

UUAAAUCU

[AAAUCUUU

AAUCUULU

UUUUCCCG

LTUCCCGGG

UCCCGGGA

CCCGGGAG

CCGGGAGU

UUCtJGUUG

CUGUUGUC

UGUUGUCU

GUCUGUUUT

UGUTUUACC

UACCAUCC

ACCAUCCA

CCAUCCAA

CAAAGCAU

UUUAACAU

UAACAUGU

AACAUGUG

ACAUGUGU

AGUGGGGG

4698 CAGAAGCC CUGAUGA X GAA AGCGCCAC GUCCUJGCCG GUGGCGCUU GGCUUCUG 176 4703 GGCCUCAG 4704 UGGCCUCA 4720 GAACUGAU 4723 GAGGAACU 4727 ACUAGAGG 4728 CACUAGAG 4731 UCUCACUA 4733 CAUCUCAC 4745 AUGACCUC 4751 UUGGGUAU 4754 AGCUUGGG 4763 AGGCCUGC 4777 AGUAUGCG 4778 CAGUAUGC 4783 GUGAGCAG 4789 CUCCCCGU 4799 GACCACUJ 4800 GGACCACU 4807 CCAAACUG

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

GAA AACUGAUG GAA AGGAACUG GAA AGAGGAAC GAA AUGCAUCU GAA ACCUCAAU GAA AUGACCUC GAA AGCUUGGG GAA AGGUCAGG GAA AAGGUCAG GAA AUG CGAAG GAA AGCAGUAU GAA ACUCCCCG GAA AACUCCCC GAA ACCACUUA GAA ACUGGACC GAA AACUGGAC GAA AGGCCAAA GAA ACUAGGCC GAA ACCUUACU GAA AGGCAACC GAA AGCCCAUC GAA AUGUGGCU GAA AAUGUGGC GAA AAAUGUGG GAA AAAAUGUG GAA ACCUGUUU GAA AACCUGUU GAA AAACCUGU CUGAUGA X GAA AGCCAAGC CUGAUGA X GAA AAGCCAAG CUGAUGA X GAA AUGGCUCU CUGAUGA X GAA AUGAUGGC CUGAUGA X GAA ACUGAUGA GCUUGGCUU CUGAGGCC CUUGGCUUC UGAGGCCA AGAGCCAUC AUCAGUUC GCCAUCAUC AGUUCCUC UCAUCAGUU CCUCUAGU CAUCAGtJUC CUCUAGUG CAGUUCCUC UAGUGAGA GUUCCUCUA GUGAGAUG AGAUGCAUU GAGGUCAU AUUGAGGUC AUACCCAA GAGGUCAUA CCCAAGCU CCCAAGCUU GCAGGCCU CCUGACCUU CGCAUACU CUGACCUUC GCAUACUG CUUCGCAUA CUGCUCAC AUACUGCUC ACGGGGAG CGGGGAGULJ AAGUGGUC GGGGAGUUA AGUGGUCC UAAGUGGUC CAGUUUGG GGUCCAGUU UGGCCUAG GUCCAGUUU GGCCUAGU UUUGGCCUA GUAAGGUU GGCCUAGUA AGGUUGCC AGUAAGGILTU GCCUACUG GGUtJGCCUA CUGAUGGG GAUGGGCUC AAAAGCCA AGCCACAUU UUAAACAG GCCACAUTUU UAAACAGG CCACAUUUU AAACAGGU CACAUUTUUA AACAGGLU AAACAGGUU UUAUCUCA AACAGGtIUU UAUCUCAA ACAGGUUTUU AUCUCAAG 4812 4813 4819 4822 4827 4832 4843 4855 4856 4857 4858 4866 4867 4868 CUAGGCCA CUGAUGA X ACUAGGCC CUGAUGA X AACCUUAC CUGAUGA X GGCAACCU CUGAUGA X CAGUAGGC CUGAUGA X CCCAUCAG CUGAUGA X UGGCUUULT CUGAUGA X CUGLUUAA CUGAUGA X CCUGUUUIA CUGAUGA X ACCUGUUU CUGAUGA X AACCUGUU CUGAUGA X UGAGAUAA CUGAUGA X UTUGAGAUA CUGAUGA X CUUGAGAU CUGAUGA X 177 4869 ACLTIGAGA CUGAUGA X GAA AAAACCUG CAGGUUUTUA UCUCAAGU a 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

AUACUTUG.

UAAUACU

UAUALTUAk

UAUAUAU

CUAUAUAI

UGUCUAU)

CUUGUCU)

GUCUUGU(

UAAUGCA.

AUAAUGC;

AACAGGAL

AAACAGG.P

UAAAACAG

AUAUAUAA

GAUAUAUA

GGAUAUAU

UGGAUAUA

AUUGGAUA

UCAUTUGGA

AUUCALTUG

CCCAGUUIA

GCCCCAGU

UGACUCUU

AUGACUCU

UAGACCAU

CUUUUCUA

CCCUUUC

UACAGAGA

GUACAGAG

GGUACAGA

UGGGUACA

A. CUGAUGA U CUGAUGA k CUGAUGA J CUGAUGA J CUGAUGA k. CUGAUGA k. CUGAUGA

CUGAUGA

J CUGAUGA

CUGAUGA

JCUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA)

CUGAUGA)

CUGAUGA)

CUGAUGA CUGAUGA Y~ CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X CUGAUGA X X GAA AUAAAACC X GAA AGAUAAAA K GAA ACUUGAGA K GAA AUACUUGA K GAA AAUACUUJG (GAA AtJUAAUAC CGAA AUAUUAAU C GAA AUAUAUUA I GAA AGUGUCUU CGAA AAGUGUCU GAA AUG CAUAA GAA AAUGCAUA GAA AUAAUGCA GAA ACAGGAUA GAA AACAGGAU GAA AAACAGGA GAA AAAACAGG GAA AUAAAACA GAA AUAUAAAA GAA AUAUAUAA GAA AUTUCALUJG GAA AUAUUCAU GAA ACUCGCCC GAA AACUCGCC GAA ACUCUUAA GAA ACCAUGAC GAA AGACCAUG GAA ACCCCUIJ GAA AACCCCUU GAA AAACCCCU GAA AGAAACCC

GGUUUUAUC

UUEJUAUCUC

UCUCAAGUA

UCAAGUAUU

CAAGUAUTUA

GUAUUAAUA

AUUAAUAUA

UAAUAUAUA

AAGACACUU

AGACACUTUA

UUAUGCAU

UAUGCAUUA

UGCAUUAUC

UAUCCUGUJ

AUCCUGUUU1

UCCUGUUUU

CCUGUUUUA1 UGUUtJUAUA

UUUUAUAUA

UtJAUAUAUC( CAAUGAAUAt AUGAAUAUA I

GGGCGAGU

GGCGAGUUA

UUAAGAGUC P~

GUCAUGGUC

CAUGGUCUA

AAAGGGGUU U

AAGGGGUUUC

AGGGGUTUUC U GGGtUtUtCUC U

UCAAGUAU

AAGUAUTUA

UUAAUAUA

AAUAUAUA

AUAUAUAG

UAUAGACA

UAGACAAG

GACAAGAC

AUGCAUTUA

UGCAUUTAU

AUCCUGLU

UCCUGUUUJ

CUGiUUUTA

LUAUAUAU

LAUAUAUC

kUAUAUCC

JAUAUCCA

JAUCCAAU

JCCAAUGA

:AAUGAAU

JAACUGGG

~CUGGGGC

~AGAGUCA

LGAGUCAU

LUGGtJCUA rAGAAAAG

AAAAGGG

CUCUGUA

UCUGUAC

CUGUACC

GUACCCA

4982 GAUUUGGG CUGAUGA X GAA ACAGAGAA UUCUCUGUA CCCAAAUC 178 4990 ACCAGCCC CUGAUGA X GAA AUUUGGGU 4999 5029 5032 5039 5041 5044 5045 5048 5053 5056 5066 5074 5082 5083 5085 5087 5088 5089 5092 5093 5096 5103 5104 5105 5111 5122 5134 5141 5143 5151 5153 5154

CUEJGGUCC

GCUGGGAC

AUAGCUGG'

AGUAACUA

UUAGUAAC

AGUUUAGU

UAGUUTUAG

GAGUAGUU

UGGGUGAG

CUUUGGGU

GAGGUCCC

AAGCCAGU

GUAAAGAG

AGUAAAGA

GAAGUAAA

AUGAAGUA

GAUGAAGU

UGAUGAAG

CCAUGAUG

UCCAUGAU

AAAUCCAUC

GAUGGUGA C GGAUGGUG c GGGAUGGU C UGCCUUGG C UCCUCUCA C

AUACUCUUC

UGGGCUGA C UAUGGGCU C UtTAAUAAA C GCUUAAUA C UGCUUAAU C CUGAUGA X GAA ACCAGCCC CUGAUGA X GAA ACCACUCU CUGAUGA X GAA ACAACCAC CUGAUGA X GAA AGCUGGGA CUGAUGA X GAA AUAGCUGG CUGAUGA X GAA ACUAUAGC CUGAUGA X GAA AACUAUAG CUGAUGA X GAA AGUAACUA CUGAUGA X GAA AGIJUUAGU CUGAUGA X GAA AGUAGUULJ CUGAUGA X GAA ACUUUIGGG CUGAUGA X GAA AGGUCCCA CUGAUGA X GAA AGCCAGUG CUGAUGA X GAA AAGCCAGU CUGAUGA X GAA AGAAGCCA CUGAUGA X GAA AGAGAAGC CUGAUGA X GAA AAGAGAAG UGAUGA X GAA AAAGAGAA :UGAUGA X GAA AGUAAAGA :UGAUGA X GAA AAGUAAAG UGAUGA X GAA AUGAAGUA ~UGAUGA X GAA AUCCAUGA ~UGAUGA X GAA AAUCCAUG UGAUGA X GAA AAAUCCAU UGAUGA X GAA AUGGUGAA UGAUGA X GAA ACUGCCUU 'UGAUGA X GAA AGCUCCUC UGAUGA X GAA ACUCtJUUA UGAUGA X GAA AUACUCUU UGAUGA X GAA AUGGGCUG JGAUGA X GAA AUAUGGGC GAUGA X GAA AAUAtJGGG ACCCAAAUC

GGGCUGGU

GGGCUGGUU

GGACCAAG

AGAGUGGUU GUCccAGc GUGGUUGUC CCAGCUAU UCCCAGCUA

UAGLJUACU

CCAGCUAUA

GUUACUAA

GCUAtJAGUU

ACUAAACU

CUAUAGUUA

CUAAACUA

UAGUUACUA

AACUACUC

ACUAAACUA

CUCACCCA

AAACUACUC

ACCCAAAG

CCCAAAGUU

GGGACCUC

UGGGACCUC

ACUGGCUU

CACUGGCUU CUCtJUUAC ACUGGCUTUC

UCUUUTACU

UGGCUUCUC

UEJUACUUC

GCUUCUCUU

UACUUCAU

CUUCUCUUU ACUUCAUC UUCUCtJUUA CUtJCAUCA UCUUUACUU

CAUJCAUGG

CUUUACUUC

AUCAUGGA

UACUtJCAUC AUGGAUUU UCAUGGAUU

UCACCAUC

CAUGGAUUU

CACCAUCC

AUGGAUUUC

ACCAUCCC

UUCACCAUC

CCAAGGCA

AAGGCAGUC

UGAGAGGA

GAGGAGCUA

AAGAGUAU

UAAAGAGUA

UCAGCCCA

AAGAGUAUC

AGCCCAUA

CAGCCCAUA

UUUAUUAA

GCCCAUAUU UAUtJAAGC CCCAUALTUU AUUJAAGCA 179 5155 5157 5158 5165 5166 5167 5172 5175 5195 5198 5199 5200 5209 5213 5215 5221 5227 5233 5235 5236 5239 5250 5273 5275 5277 5278 5280 5281 5282 5283 5286 5290 5291

GUGCUAA

AAGUGCUU

AAAGUGCU

GGAGCAUA

AGGAGCAU

AAGGAGCA

GUGCCAAG

GCUGUGCC

GCAUAAAU

CLTUGCAUA

GCUUGCAU

AGCUUGCA

UGGAGAGG

UAGCUGGA

CCUAGCUG

CUGAGUCC

AAUAUCCU

UTUGACUAA

CATJUGACU

UCAUUGAC

GGCUCAUU

LUCCUUUU

AAAUAAGA

GAAAAUAA

AUGAAAAU

GAUGAAAA

CAGAtJGAA

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:

CUGAUGAI

CUGAUGA

CUGAUGAI

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA I CUGAUGA I GAA AAAUAUGG GAA AUAAAUAU *GAA AAUAAAUA *GAA AGUGCUUA *GAA AAGUGCUU GAA AAAGUGCU GAA AGCAUAAA GAA AGGAGCAU GAA ACACAUCA GAA AUUACACA GAA AAUUACAC GAA AAAUUACA GAA AGCUUGCA GAA AGGGAGCU GAA AGAGGGAG GAA AGCUGGAG GAA AGUCCUAG GAA AUCCUGAG GAA AUAUCCUG GAA AAUAUCCU GAA ACUAAUAU GAA AUGGCUCA GAA AGGUEUUU GAA AUAGGLUU GAA AGAUAGGU GAA AAGAUAGG GAA AUAAGAUA GAA AAUAAGAU GAA AAAUAAGA GAA AAAAUAAG GAA AUGAAAAU GAA ACAGAUGA GAA AACAGAUG CCAUAtUUUP

AUAUUUAUL

UAUUTUAUUP

UAAGCACUU

AAGCACUUU

AGCACUUUA

UUUAUGCUC

AUGCUCCUJ

UGAUGUGUA

UGUGUAAUU

GUGUAALTUU

UGUAAUTUUA

UGCAAGCUC

AGCUCCCUC

CUCCCUCUC

CUCCAGCUA

CUAGGACUC

CUCAGGAUA

CAGGAUAUU

AGGAUALTJA

AUALUAGUC

UGAGCCAUC

AAAAACCUA

AAACCUAUC

ACCUAUCTJ

CCUAUCtJUA

UAUCUULAUU

AUCUTUAUU

UCLTrJAUUUJ CUtJAUUUUC

AUUUUCAUC

UCAUCUGUU

CAUCUGUU

LUUAAGCAC

fAAGCACUIJ

AGCACUUUJ

UATJGCUCC

AUGCUCCU

.UGCUCCUU

CUUGGCAC

GGCACAGC

AUUUAUGC

UAUGCAAG

AUG CAAG C

UGCAAGCU

CCUCUCCA

UCCAGCUA

CAGCUAGG

GGACUCAG

AGGAUALU

UUAGUCAA

AGUCAAUG

GUCAAUGA

AAUGAGCC

AAAAGGAA

UCUUAUUU

UTUAUUUUC

AUULUUCAU

UUUUCAUC

UTUCAUCUG

UCAUCUGU

CAUCUGLU

AUCUGULU

UGUTUUCAU

UCAUACCU

CAUACCUU

180 5292 CAAGGUAU CUGAUGA X GAA AAACAGAU AUCUGUUUC AUACCUTUG

S.

S.

S

*5

S

S

S

S

5295 5299 5302 5309 5311 5331 5350 5367 5369 5370 5376 5378 5395 5397 5399 5408 5410 5412 20 5413 5419 5422 5432 5433 5438 5447 5448 5452 5475 5497 5504 5505 5524

AGACAAGC

CCCCAGA(

AGACCCCI

CGUCALUM

AUCGUCAt.

CCCAUGUC

ccUtUUuc

ACCCCAA.

AGACCCCA

UAGACCCC

CAUCtJCUA

CUCAUCUC

AIJUUUAGA

CCAUUtJUA

AGCCAUU

UUCUAAGA

ACUUCUAA

CAACUUCU

ACAACUTUC

GCACAUAC

UUUTGCACA

CAGACCAU

ACAGACCA

AGCACACA

CACGACCU

GCACGACC

GUGUGCAC

CCAGCUGU

AAAGCAGC

CUCUCCCA

GCUCUCCC

UAAGUGGC

3CUGAUGA

CUGAUGA

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

CUGAUGA2 CUGAUGA2

CUGAUGA

GA)V

GA7

GA-

GAP

GAP

GAP

GA?

GAA

GAA

GAA

GAA

GAA

GAA

GA?

GA?

GA?

GA?

GA?

GA?

GA?

GA?

GA?

GA?

GA?

GAA

GJA?

GAA

GA?

GAA

GAj

GA)

GA)

~AUGAAACA

SAGGUAUGA

\ACAAGGUA

SACCCCAGA

AGACCCCA

ACCCUGUU

ACCCUGUC

AGCGGGCA

AGAGCGGG

AGAGCGG

ACCCCAAA

AGACCCCA

ACCCAGGG

AGACCCAG

AGAGACCC

AGCCAUUU

AGAGCCAU

AGAGAGCC

AAGAGAGC

ACUUJCUAA

ACAACUUC

AUUTUGCAC

AAUTLYJGCA

ACCAUAAU

AGCACACA

AAGCACAC

ACCUAAGC

ACCGGCUC

ALUJCAUCG

AGCAGCUA

AAGCAGCU

AGCAUGCU

UGUUUCAU)

UCAUACCLt

UACCUUGUC

UCUGGGGUC

UGGGGUCU7 AACAGGGUz

GACAGGGUP

UGCCCGCUC

CCCGCUCUJ

CCGCUCUUUJ

UUUGGGGUC

UGGGGUCUA

CCCUGGGUC

CUGGGUCUC

GGGUCUCUA

AAAUGGCUC

AUGGCUCUC

GGCUCUCUU

GCUCUCUUA

UtJAGAGUU

GAAGUUTGUA

GUGCAAALU

UGCAAALTUA

AUtJAUGGUC

UGUGUGCUU

GUGUGCUUA

GCUtJAGGUC

GAGCCGGUC

CGAUGAUA

UAGCUGCUU

AGCUGCUU

AGCAUGCUA

kCCUUGUCU J GUCUGGGG

UGGGGUCU

UAAUGACG

AUGACGAU

GACAUGGG

GAAAAGGG

UUUGGGGU

UGGGGUCU

GGGGUCUA

UAGAGAUG

GAGAUGAG

UCUAAAAU

UAAAAUGG

AAAUGGCU

UCUUAGAA

UUAGAAGU

AGAAGUUG

GAAGUUGU

GUAUGUGC

UGUGCAA

AUGGUCUG

UGGUCUGU

UGUGUGCU

AGGUCGUG

GGUCGUGC

GUGCACAC

ACAGCTGG

GCUGCUUU

UGGGAGAG

GGGAGAGC

GCCACUUA

a.

C

b.C.

C C C.

C.

5531 5532 5535 5536 5538 5554 5561 5568 5577 5584 5587 5588 5593 5594 51595 5596 5600 5627 5660 5662 5671 5685 5693 5704 5705 5707 5731 5736 5754 5756 5757 5760 5764

AGAGAAU

CAGAGAAI

GGUCAGA(

CGGUCAGj

CCCGGUCJ

GUACCCAI

GGAGCAGC

ACACAGGC

GGAUGGGC

ACCUUAAC

AAAACCUL

GAAAACCL

AGACAGAA

CAGACAGA

IJCAGACAG

AUCAGACA

UCUCAUCA

UCAGUGGG

UGCACCAA

AGUGCACC

UGGCUGGU

UACUUGUC

CCCTuurjCC

GUGGCUAG

UGUGGCUA

AGUGUGGC

CCCUACCU

GCCAGCCC

UGGACAAA

AAUGGACA

GAAUGGAC

UGCGAAUG

CUUUUGCG

LI CUGAUGA JI CUGAUGA 3 CUGAUGA rl CUGAUGA k CUGAUGA J CUGAUGA .7 CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

iCUGAUGA rCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA.

CUGAUGA:

CUGAUGA:

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA:

CGAUGA

CUGAUGA I CUGAUGA I CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA 2 CUGAUGA 2~ CUGAUGA Y~ CUGAUGA Y X GAA AGUGGCUA X GAA AAGUGGCU K GAA AUTUAAGUG K GAA AAUUAAGU K GAA AGAAUUAA CGAA AUG CUGGC C GAA ACCCAUGA C GAA AGCAGGUA I GAA ACACAGGG CGAA AUGGGGUA GAA AGGAUGGG GAA AAGGAUGG GAA ACCUUAAG GAA AACCUUAA GAA AAACCUUA GAA AAAACCUU GAA ACAGAAAA GAA AUUGCACU GAA AGCCACAG GAA AGAGCCAC GAA AGUGCACC GAA AGUCCUGG GAA ACUIJGUCU GAA AGCCCUUIJ GAA AAGCCCUIJ GAA AGAAGCCC GAA AUUUUTCUU GAA ACCUGAULI GAA AUGUCUUU GAA AGAUGUCU GAA AAGAUGUC GAA ACAAAGAU GAA AUGGACAA

UAGCCACU

AG CCACUU, CACUUAAtf ACtJUAAUU(

UUAAU-UCU(

GCCAGCAUC

UCAUGGGUI

UACCUGCU(

CCCUGUGUI

UACCCCAUC

CCCAUCCUT

CCAUCCUUP

CUUAAGGUE

UUAAGGUUU

UAAGGUUUU

AAGGUUULJC

UUUUCUGUC

AGUGCAAUC

CUGUGGCUC

GUGGCUCUUt

GGUGCACUC

CCAGGACUA

AGACAAGUA

AAAGGGCUU

AAGGGCUUC

GGGCUUCUA

AAGAAAAUC

AAUCAGGUA

AAAGACAuc

AGACAUCUU

GACAUCUUIJU

AUCUUUGuc UUGUCCAL71 UI AAUUCUCU k AUUCUCUG JL CUCUGACC

:UCUGACCG

7UGACCGGG

SAUGGGUAC

k~ CCUGCUCC

CCCUGUGU

SCCCCAtJCC

CUUTAAGGU

TAAGGULUU

AGGUUTUUC

UUCUGtJCU

UCUGUCUG

CUGUCUGA

UGUCUGAU

UGAUGAGA

CCCACUGA

UUGGUGCA

GGUGCACU

ACCAGCCA

GACAAGUA

GGAAAGGG

CUAGCCAC

UAGCCACA

GCCACACUL

AGGUAGGG

GGGCUGGC

UUUGUCCA

UGUCCALU

GUCCAUtJC

CAUUCGCA

CGCAAAAG

182 5765 GCUUUUtGC CUGAUGA X GAA AAUGGACA UGUCCAUTUC GCAAAAGC 6'~ es..

S

9~.

S

S.

S S

SSS*

S

.S.C

S

j~.

S

S

S. S *6*S

S

S

5 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

GCCGACA

CAGCCGA

CUGCAGC.

GCCUGAC1

CAUCGCCI

UUCUCUG(

GGAUGAG2

UGGAUGAC

CUGGAUGI

AUCUGGA.

GAUAUCUC

UUGCUGG;

AAUTUGCUC

CACCCCCC

GGACCAUC

UAAUACAG

CGGAAUAA

AUCGGAAU

AAUCGGAA

AAAAUCGG

UAA.AAUCG

AUUALTUAA

GAUUJAUUA

AGALTUtAUU

UAGAUEJAU

AAUUAGAU

ACGAAUTUA

UCACGAAU

UGAUCACG

AUGAUCAC

CUCUUAAU

A CUGAUGA C CUGAUGA C CUGAUGA LJ CUGAUGA JI CUGAUGA 3 CUGAUGA

CUGAUGA

CUGAUGA

k. CUGAUGA iCUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA:

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGAI

CUGAUGA2

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA y CUGAUGA Y CUGAUGA Y CUGAUGA X CUGAUGA X CUGAUGA X X GAA AGCUUUUG K GAA AGAGCUUU KC GAA ACAAGAGC K GAA ACACACUG GAA ACUUACAC C GAA AGCCUCUG CGAA ACCUCAGG GAA AACCUCAG GAA AAACCUCA GAA AGAAACCU GAA AUGAGAAA GAA 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 AUUAAA.AU GAA AUUAUIJAA GAA AGAIJUAUU GAA AUUAGAUU GAA AAUUAGAU GAA AUCACGAA

CAAAAGCU

AAAGCUCU

GCUCUUTGUi

CAGUGUGU

GUGUAAGU(

CAGAGGCLD

CCUGAGGLtE

CUGAGGJUT.

UGAGGLTUUC

AGGUUUCUC

UUUCUC-AUC

AUCCAGAUJA

CCAGAUAUC

CCAGCAAUU

AAGACCAUA

UAGAUGGUC

GGUCCUGUA

UCCUGUAUU

CCUGUAUUA

UGUAUUALU

GUAU.UAUUC

AUUCCGALU

UUCCGAUUJT

UCCGAUUJTJT

CCGAUJUiUA

AIJUUUAAUA

UUAAUAAUC

AAUAAUCUA

AAUCUAAUU

AUCUAAtJUC

LTUCGUGAUC

C UUTGUCGGC LI GUCGGCUG C GGCUGCAG k~ AGUCAGGC

SAGGCGAUG

\CCAGAGAA

J UCUCAUCC

JCUCAUCCA

UCAUCCAG

AUCCAGAU

CAGAUAUC

UCCAGCAA

CAGCAAUU

GGGGGGUG

GAUGGUCC

CUGUAUtJA

UUAUUCCG

AUUCCGAU

UUCCGALU

CCGALUULj

CGALUUUJA

UUtAAUAAU

UAAUAAUC

AAUAAUCU

AUAAUCUA

AUCUAAUU

UAAUUCGU

AUUTCGUGA

CGUGAUCA

GUGAUCAU

AUUAAGAG

5943 AGUCUCUU CUGAUGA X GAA AUGAUCAC GUGAUCAUTU AAGAGACU 183 5944 5952 5953 5954 5957 5963 5967 5968 5969 5970 5981 5992 5994 6000 6001 6003 6008 6009 6014 6015 6022 6023 6027 6028 6036

AAGUCUCL

AUUUACUP

CAUUtJACU

ACAUUUAC

GGGACAUU

GGAAAAGG

UGUGGGAA

TJUGUGGGA

ULTUGUGGG

UUUUGUGG

cuUUUUt-J

AAUCCCGA

AGAAUCCC

AACCAGAG

GAACCAGA

CAGAACCA

UUAAGCAG

UUTUAAGCA

AAGtJCUUU

UAAGUCUU

CCAAAGCU

UCCAAAGC

AGGCUCCA

tJAGGCUCC AACtJUUCA

ICUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CUGAUGA

CIJGAUGA

CUGAUGA

GA1A

GATA

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

ACALTUUAC

AGGGACAU

AAGGGACA

AAAGGGAC

AAAAGGGA

ACUUUUGU

AGCUUUJC

AUAGCUUU

AUCCCGAU

AAUCCCGA

AGAAUCCC

ACCAGAGA

AACCAGAG

AGCAGAAC

AAGCAGAA

AGUCUt3UA

AAGUCULU

AGCUAAGU

AAGCUAAG

AGGCUCCA

ACUUUCAU

UGAUCAL7UA

AAGAGACUU

AGAGACUUJ

GAGACUUUA

ACTJUUAGUA

GUAAAUGUC

AUGUCCCUU

UGUCCCUUU

GUCCCUUUU

UCCCUULUJC

ACAAAAGUA

GAAAAGCUA

AAAGCUAUC

AUCGGGAUU

UCGGGAUUC

GGGAUUCUC

UCUCUGGUU

CUCUGGUUC

GTJUCUGCUU

UUCUGCIJUA

UAAAGACUU

AAAGACUUA

ACUTUAGCUU

CUTUAGCUUU

UGGAGCCUA

AUGAAAGUU

*AGAGACUU

UAGUAAAU

AGUAAAUG

GUAAAUGU

AAUGUCCC

CcUUUUcC

UUCCCACA

UCCCACAA

CCCACAAA

CCACAAAA

AAGAAAAG

UCGGGAUUI

GGGAUUTCU

CUCUGGLU

UCUGGUTUC

UGGtJUCUG

CUGCUUIAA

UGCLUAAA

AAAGACUUL

AAGACUUA

AGCIJUUGG

GCUUTUGGA

UGGAGCCU

GGAGCCUA

UGAAAGUU

GAUCAGCC

6044 GGCUGAUC CUGAUGA X Where "IXI represents stem II region of a HH ribozyne (Hertel et al., 1992 Nucleic Acids Res. 20 3252) may be z 2 base-pairs.

The length of stem II C,

OC

S S S S S S

S

184 Table IX: Mouse fltl VEGF Recelptor-Hairpin Ribozyme and Substrate Sectuence nt.

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

GGUGUCCC

UAAGGCAA

GACACCCG

CUGUGAGA

GAAAGAGA

CAUGAGUG

CGGUCGUG

CUCCCACA

GGAUGAUG

CGUCACCC

CUUUGCCC

CGCAGUTUC

GCCGAUGG

UUGUAUUG

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCUGAC

GCGGUG

GCGCGU

GACACC

GGCCUG

GCCUCC

GAGACC

GAUGGG

GUCUUC

GGGGAU

GGGGUA

GUCCUA

GAUAGU

GCCGAU

ACCAGAGAAACACACGUUGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUrGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA

ACCAGAGAAA.CACACGUUIGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGLUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGJTGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJIGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGJTGUGGUACAUrJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGACACACAGUGUGGUACAUUTACCUGGUA

AUGGUCA

GUCAGCU

CACCGCG

ACGCGCU

GGUGUCU

CAGGCCA

GGAGGCA

GGUCUCU

CCCAUCG

GAAGACA

AUCCCCU

UA CCCC U

UAGGACU

ACUAUCU

AUCGGCA

GCU

GCU

GUC

GCU

GCU

GAC

GCC

GCC

GCC

GCU

GCC

GAU

GCU

GAC

GAC

GCUGGGAC

GGGACACC

LJUGCCUUA

CGGGUGUC

UCUCACAG

UCUCUUUC Ph

CACUCAUG

CACGACCG

UGUGGGAG

CAUCAUCC

GGGUGACG

GGGCAAAG

GAACUGCG

CCAUCGGC

CAAUACAA

9..

~9 9 9 9* 9 9* 9 999 99 *9 9* 9 9. 9 S. 9 99 9 9 9, '9 9 9 9 99 9 9*9 9

S

185 736 754 766 871 960 988 1051 1081 1090 1093 1169 1315 1363 1604 1612 1629 1632 1688

CUGGGCUC

GCCCGUGG

GGACAAGA

UCCGGUCA

CUUCACGC

UGUUGAAA

CCUGCACC

GCCGAUAG

UCAUGGAC

CUUUCAUG

AAAUAGCG

IJUUCGUAG

UGCUGCCC

GUCUGAGA

UUCCAGGG

GGCCCGGC

GAAGGCCC

UUCGGCAC

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

GAGGU

GAUAGA

GCCACC

GAGAGU

GUAGAU

GCUGUA

GUGACA

ACCAGAGAAACACACGUJGUGGUACAUpJACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJTACCUGGUA

ACCAGAGAAA~CACACGU1JGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGJIGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGU.UGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUU.GUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

UACGCCC

UGAGACU

ACGGGCA

GGCAGCG

UACACCU

CC UU CCA

GGAAGCA

GAAGACG

CCUAUCG

AUCGGCU

GAAGUCU

AACCUCA

UCUAUCC

GGUGGCU

ACUCUCA

AUCUACA

UACAGCU

UGUCACA

GCC

GCU

GAC

GAU

GUC

GUC

GCC

GUC

GCU

GUC

GCU

GAU

GCU

GAC

GAC

GCU

GCC

GAU

GAGCCCAG

CCACGGGC

UCUUGUCC

UGACCGGA

GCGUGAAG

IJUUCAACA

GGUGCAGG

CUAUCGGC

GUCCAUGA

CAUGAAAG

CGCUAUUU

CUACGAAA

GGGCAGCA

UCUCAGAC

CCCUGGAA

GCCGGGCC

GGGCCUUC

GUGCCGAA

1730 730UCUCCUUC AGAA GGCAUC ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA GAUGCCA GCC GAAGGAGA 0 9** 0** 0 0 0 *0 0 0 0* 00 0.

0 0 0* 0 0* 0 00 0

S

186 1753 2017 2101 2176 2258 2305 2383 2405 2 432 2464 2467 2592 2596 2653 2743 2779 2814 2831 2895

CCACACAG

GGUUUUGA

ACCAAGUG

UUUCAAUA

GUGAGGUA

UGAGCGUG

CGGAAGAA

GACAGGUA

GGAACUUC

CAUAGGGC

CAUCAUAG

CACAGUCC

CAGCCACA

GUUCGGUC

CGAUCACC

GGUAGUUG

CUUGUUGA

AUAUGCAA

ACUGUCUA

AGAA

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

GUCUU

GGGUCC

GUUCAC

GCCGUU

GGUGGG

GGCAGG

GAGCUU

GAGGCC

GGUUUC

GAAUAA

GCGUCC

GGGCUU

ACCAGAGAAACACACGUUTGUGGUACAUJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUrJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGJUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJGUGGUAcAUJACCUGGUA

ACCAGAGAAACACACGUJIGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

UGAAACU

CACACCU

CGCCUCA

GCACGCU

AAGCGCA

UGGAGCU

UGAAGCG

AAAGACA

GGACCCA

GUGAACG

AACGGCU

CCCACCU

CCUGCCG

AAGCUCU

GGCCUCU

GAAACCU

UUAIJUCU

GGACGCA

AAGCCCC

GUC

GCU

GAU

GUU

CC

GAU

GUC

GAC

GAU

GCU

GCC

GCC

GAC

GAU

GAU

GUC

GUC

GCC

GCC

CUGUGUGG

UCAAAACC

CACUUGGU

UAUrJGAAA

UACCUCAC

CACGCUCA

UUJCUUCCG

UACCUGUC

GAAGUUCC

GCCC.UAUG

CUAUGAUG

GGACUGUG

UGUGGCUG

GACCGAAC

GGUGAUCG

CAACUACC

UCAACAAG

UUGCAUAU

UAGACAGU

C C C C C C. C C C. *C C. C C C C. C C C C C C C C. C C *CC

C

187 2913 2928 2934 3001 3022 3033 3064 3179 3357 3360 3379 3463 3496 3553 3615 3623 3650 3754 3772

GACACIJUG

GAAGCUGG

UUCAGGGA

UGGUGAGG

UGUAGGAA

CACIJUGGA

UUCUGGAG

CUCACAUA

CUUCAGGC

UUCCUIJCA

GGGUUCUC

GUUCAGCA

UGGCUUGA

UGUUUCUA

AUCUGCAA

AAAUGUGG

CUCACAUC

UAGUGUCC

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GCUGAC

GGUGAC

GGAGCU

GCUUGO

GGUCUU

GUAGGA

GAAACU

GGGUUC

GCAGAA

GCUGCA

GCAUGC

GGGGCC

GGUCAC

GUAUGG

GUCCUU

GCAAAG

GAGCUU

GAUAGU

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUtGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJIACCUGGUA

ACCAGAGAAA~CACACGUUGUGGUACAUJ1ACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUIJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAIYJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJ1ACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

GUCAGCA GCU GUCACCA GCU AGCUCCA GCU CCAAGCA GCC AAGACCU GAU UCCUACA GUU AGUUUCU GUC GAACCCU GAU UtJCUGCA CC UGCAGCC GCC GCAUGCG GAU GGCCCCG GUU GUGACCU GCU CCAUACU GAC AAGGACG GCU CUUUGCA GAU AAGCUCU GAU ACUAUCA GCU

CAAGUGUC

CCAGCUUC

UCCCUGAA

CCUCACCA

UUCCUACA

UCCAAGUG

CUCCAGAA

UAUGtJGAG

GCCUGAAG

UGAAGGAA

GAGAACCC

UGCUGAAC

UCAAGCCA

UAGAAACA

UUGCAGAU

CCACAUUUJ

GAUGUGAG

GGACACUA

GGGAGCCC AGAA GAGUGC ACCAGAGAAACACACGtJUGUGGUACAU!JACCUGGUA GCACUCU GCU GGGCUCCC S* S S S

S

555 5* 55 S 5 55 5 55 55 S. S 55 S S S S S S S S S S S S S S S 188 3796 3881 3886 3897 3903 3912 3969 3972 3986 4018 4022 4040 4053 4095 4110 4113 4168 4290 UCCAGGUG AGAA CUCGGCAG AGAA UGGGCCUC AGAA GAAGCAGA AGAA GCUGGAGA AGAA GTJGGCCAC AGAA UGGAGAAC AGAA GGGUGGAG AGAA GAGUUGUA AGAA UUUAGGCG AGAA AAGCUUUA AGAA GUUGUCGG AGAA CUGUCAGG AGAA UCCUGUGG AGAA CGAAAAGC

AGAA

UCACGAAA AGAA UUAGUCAA AGAA GGUGGGCG AGAA GCUUCA ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA GAAAGU ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GAUCGG ACCAGAGAAACACACGUJIGUGGUACAUJTACCUGGUA GGGCCU ACCAGAGAAACACACGUIJGUGGUACAU1JACCUGGUA GAAGCU ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA GGAGAA ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GGACUC ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA GCAGGA ACCAGAGAAACACACGUJGUGGUACAUJ1ACCUGGUA GGGGGU ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA GGGAGG ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA GGCGGG ACCAGAGAAACACACGUIJGUGGUACAUUACCUGGUA GGUGAG ACCAGAGAAACACACGUUGUGGUACAJUACCUGGUA GGUUGU ACCAGAGAAACACACGUJGUGGUACAUTJACCUGGUA GAAUAG ACCAGAGAAACACACGUJTGUGGUACAUJACCUGGUA GGCUCC ACCAGAGAAACACACGUUrGUGGUACAUJTACCUGGUA GCUGGC ACCAGAGAAACACACGUJGUGGUACAUJTACCUGGUA GCAACA ACCAGAGAAACACACGUUGUGGUACAUJ1ACCUGGUA GUCGCC ACCAGAGAAACACACGUUGUGGUACAUJTACCUGGUA

UGAAGCG

ACUIJUCC

CCGAUCU

AGGCCCA

AGCUUCU

UUCUCCA

GAGUCCU

UCCUGCU

ACCCCCA

cCUccc

CCCGCCC

CUCACCA

ACAACCA

CUAUUCC

GGAGCCA

GCCAGCU

UGUUGCU

GGCGACC

GUTJ

GAU

CC

GCU

GCU

GCU

GCU

GU

GAC

GCC

CC

CC

GCC

GCU

GCU

GCU

GLU

GCC

CACCUGGA

CUGCCGAG

GAGGCCCA

UCUGCUUC

UCUCCAGC

GUGGCCAC

GUUCUCCA

CUCCACCC

UACAACUC

CGCCUAAA

UAAAGCUU

CCGACAAC

CCUGACAG

CCACAGGA

GCU!JUUCG

UUUCGUGA

tJUGACUAA

CGCCCACC

1 4294 494GGCCGGUG AGAA GGCGGU ACCAGAGAAACACACGUUGUGGUACAUTJACCUGGUA ACCGCCC GCC CACCGCC S. **4

S

4 44* S *4 4* 4 54 4 *4 4 4 4 44 *4 9 4 189 4329 4378 4383 4388 4457 4525 4528 4643 4650 4724 4771 4785 4809 4834 4912 5119 5144 5287 5363

AGUCCCAC

CAGAGCAG

AGAGACAG

AUAAGAGA

CUCCACAG

CCCGAAAC

GGGCCCGA

AAACAGAC

GGAUGGUA

ACUAGAGG

AUG CGAAG

UCCCCGUG

CUAGGCCA

IUCGAGCCC

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

GAUGAU

GGCCUG

GUAUGC

GGA CCA

GUAGGC

GGAUAA

GCCUUG

GAUACU

GAUGAA

ACCAGAGAAACACACGUUGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUTGUGGUACAUTJACCUGGUA

ACCAGACAAACACACGUJGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUrACCUGGUA ACCAGAGAAA CACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUIJACCUGGuA ACCAGAGAAACACACGUrGUGGUACAUUACCUGGUA

ACCAGAGAAACACACGUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUIGUGGUACAUTJACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUrACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJACCUGGUA

CCCUGCA GCU AUGCACU GAC CUGACCU GCU CUGCUCU GUC UGCGUCC GUC GGCCUCC GCU CUCCGCU GUU GUCUTUCU GU1J GUUGUCU GUU AUCAUCA GUU CAGGCCU GAC GCAUACU GCU UGGUCCA GUU GCCUACU GAU UUAUCCU GUU CAAGGCA GUC AGUAUCA GCC UUCAUCU GUU GGUGCCC

GCU

GUGGGACU

CUGCUCUG

CUGUCUCU

UCUCUUAU

CUGUGGAG

GUUUCGGG

UCGGGCCC

GUCUGULJU

UACCAUCC

CCUCUAGU

CUUCGCAU

CACGGGGA

UGGCCUAG

GGGCUCAA

UUAUAUAU

UGAGAGGA

CAUAUJUA

UCAUACCU

CULJUGGGG

CCCCAAAG AGAA GGCACC 4 4* *4 4 *44 U *4 4 444* *4 4 4 4* U 4. 4 4 4 4*UU 4 44 4 *44 4 190 5462 5478 5486 5500 5539 5564 5597 5601 5639 5646 5781 5829 5842 5915 6010 CCGGCUCC AGAA GGUGUG ACCAGAGAAACACACGUTJGUGGUACAUUACCUGGUA CACACCU GCC GGAGCCGG

"P

GUCUGCCC

UAUUCAUC

UCUCCCAA

CUGGCCCG

CACAGGGG

UCUCAUCA

CCAGUCUC

GGGCUGCA

CCACAGUG

CACACUGC

CUGUTUCUC

AAAC CU CA

LUUAUTUAAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

AGAA

GUGACC

GCCCAG

GCUAUU

GAGAAU

GGUACC

GAAAAC

GACAGA

GUCUCA

GCAGGC

GACAAG

GUUUCU

GCUGUU

GAAUAA

ACCAGAGAAACACACGUUUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

ACCAGAGAAACACACGUUUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUUGJUGGUACAIJUACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJIGUGGUACAUUTACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUJTACCUGGUA

ACAAAAAAGUGGUCUACGU

ACCAGAGAAACACACGUUGUGGUACAUUtACCUGGUA

ACCAGAGAAACACACGUJGUGGUACAUUACCUGGJA

ACCAGAGAAACACACGUJGUGGUACAUUIACCUGGUA

ACCAGAGAAACACACGUUGUGGUACAUJACCUGGUA

GGUCACA

GCU

CUGGGCA GAC AAUAGCU GCU AUUCUCU GAC GGUACCU

GCU

GUUTUUCU GUC UCUGUCU GAU UGAGACA GCC GCCUGCA GCC CUUGUCG GCU AGAAACG GAU AACAGCA GCC

GGGCAGAC

GAUGAAUA

UUGGGAGA

CGGGCCAG

CCCCUGUG

UGAUGAGA

GAGACUGG

UGCAGCCC

CACUGUGG

GCAGUGUG

GAGAACAG

UGAGGUUU

AGUCIJUUA AGAA GAACCA ACCAGAGAAACACACGUUGUGGUACAUUTACCUGGUA UGGUUCU GCU UAAAGACU 191 Table X: Homologous Hammerhead Ribozyme Target Sites Between Human fit-i and KDR RNA

*S.

nt.

Posi t ion 3388 2174 2990 2693 2981 1359 3390 3391 2925 7140 1785 2731 3974 6590 6705 974 1872 2333 2775 3533 3534 3625 1814 2744 2783 fit-i Target Sequence CCGGGAU A IJUUAUAA AAUGUAU A CACAGGG UGCAAAU A UGGAAAU CUCCCUU A UGAUGCC GUIJGAAU A CUCCAAA UAUGGUU~ A AAAGAUG GGGATJAU U UAUAAGA GGAUAUU U ATJAAGAA ACGUGGU U AACCUGC UAUUTUCU A GUCAUGA CAATJAAU A GAAGGAA GAGACUU A AACUGGG GAUGACU A CCAGGGC UTUAAUGU A GAAAGAA GCCAUUU A UGACAAA GUCAAAU U ACUUAGA AUAAAGU U GGGACUG ACUUGGU U UAAAAAC AAGUGGU U CAAGCAU UUCUCCU U AGGUGGG UCUCCUIJ A GGUGGGU GUACUCU A CUCCUGA AGCACCU U GGUUGUG GGCAAAU C ACUTUGGA CAAGCAU C AGCAUUtJ nt.

Posi 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

CUgCCUU GUgGAAU UgUGGUU

GGGAUAU

GGAUALU

AuGUGGU UAcUUCU CucUAAU uuGACUU GAgGACU aaAAUGU a CaAUTU uUCAAAU AcAAAGU AaaUGGU AcaUGGU

LUUUCCU

UuUCCUU GagCUCU AGuACCU uuCAAAU gAAGCAU A UIJAUAA c CACAGGG u UGGAAAc A UGATJGCC u CUGCAAA u AAAGAUa U UAUAAag U AUAAagA c AACCUuC uGUCAUcA u GAAGGAA c AACIJGGG u CCAGGGa u GAAAGAA u UGACAgA U ACUUgcA GGGAgaG a UAAAAAu a CAAGCuU U AGGUGcu.

A GGUGcuU c CUCCUGu U GGUJTacc u ACUUJGcA C AGCAUaa

KDR

Target Sequence 192 3613 GAGAGCU C CUGAGUA.

4052 5305 7158 1836 2565 4250 7124 436 2234 2763 4229 5301 6015 6095 6236 5962 7629 AAGGCCU C UCUCCAU A AUGUAUU U CUAGAAU U CUcuCUU C CUGUACU C ACAUGGU U AUGGUCU U GCACCAU A GGGCUUU U CCAGACU A GUULUCU C AGAAUGU A AUUCCCU A UGUUGtJU C GCUUCCU U UAUAUAU U

GCUCAAG

tJCAAAAC

UGUAUAC

UCUGGAA

IJGGCUCC

CACCCCA

UGGUCCU

UGCCUGA

CCUCCUG

GGAAAAG

CAACUCG

CAUAUCA

UGCCUCU

GUGAGCC

cUcUUCU

UUAUCCA

CIJCUGCU

2968 1923 456 631 1007 2328 3388 3778 1337 1344 990 767 3307 1917 1438 76 3099 3096 GgaAGCU C ucuGCCU u ggUCCAU u gUcUAUU a allgGAAU c uguUCUU C uUaUACU a cagUGGU a AcGGUCU a augCCAU u uuGCUUU U auuGACU u ugcUUCU C AcuAUGU c AUaCCCU u UagUGUU u auaUCCU c gAaAUAU c CUGAagA.

GCUCAAG

UCAAAuC UGUAcAu UCUGGug UGGCUaC CACCagA IJGGUuCU UGCCauu

CCUCCCC

GGAAguG CAACUgG CAUAUCc UGCCUug GUGAaga CUCUga UUJAUCgg CUCUuaU Lowercase letters are used to represent sequence variance between fit-i and KDR RNA 193 Table XI: 2.5 umol RNA Synthesis Cycle Reagent Equivalents Amount Phosphoramidites 6.5 163jiL S-Ethyl Tetrazole 23.8 2381IL Acetic Anhydride 100 233 ML N-Methyl Imidazole 186 233 yiL TCA 83.2 1.73 mL Iodine 8.0 1.18 mL Acetonitrile NA 6.67 mL Wait Timne* 5 sec 5 sec 21 sec 45 sec

NA

S

Claims (40)

1. An isolated enzymatic nucleic acid molecule which specifically cleaves fit-i RNA at site 4229.

2. The enzymatic nucleic acid molecule of claim 1, wherein the enzymatic nucleic acid molecule is chemically synthesized.

3. The enzymatic nucleic acid molecule of claim 1 or claim 2, which is in a hammerhead motif.

4. The enzymatic nucleic acid molecule of any one of claims 1 to 3, which comprises between 12 and 100 bases complementary to the RNA encoding the fit-i receptor. The enzymatic nucleic acid molecule of any one of claims 1 to 3, which comprises between 14 and 24 bases complementary to the RNA encoding the fit-i receptor.

6. An isolated enzymatic nucleic acid molecule which specifically cleaves fit-i RNA at site 4229, substantially as hereinbefore described with reference to any one of Examples 3, 5, 7, 10 and 11.

7. An isolated enzymatic nucleic acid molecule which specifically cleaves fit-i RNA at site 4229, substantially as hereinbefore described with reference to Table II.

8. An isolated enzymatic nucleic acid molecule which specifically cleaves fit-l RNA at site 4229, substantially as hereinbefore described with reference to the accompanying drawings Figs 11A and 12A.

9. An expression vector comprising a nucleic acid sequence encoding the enzymatic nucleic acid molecule of any one of claims 1 to 8 in a manner which allows expression or delivery of said nucleic acid molecule within a mammalian cell.

10. A mammalian cell comprising the enzymatic nucleic acid molecule of any one of claims 1 to 8, wherein said mammalian cell is not a living human.

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

12. A mammalian cell according to claim 10 or claim 11, which is a 30 microvascular endothelial cell.

13. A mammalian cell as defined in claim 10, substantially as hereinbefore described with reference to Example 5 or Example

14. A mammalian cell comprising the expression vector of claim 9, wherein said mammalian cell is not a living human.

15. The mammalian cell of claim 14, which is a human cell. A02409 195

16. A mammalian cell according to claim 14 or claim 15, which is a microvascular endothelial cell.

17. A composition comprising the enzymatic nucleic acid molecule of any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

18. A composition as defined in claim 17, substantially as hereinbefore described with reference to Example 5 or Example 11.

19. A composition comprising the expression vector of claim 9 and a pharmaceutically acceptable carrier. A method of cleaving RNA of the fit-1 gene comprising the step of contacting 1o said RNA with the enzymatic nucleic acid molecule of any one of claims 1 to 8, under conditions suitable for the cleavage of said RNA.

21. The method of claim 20, wherein said enzymatic nucleic acid molecule comprises between 12 and 100 bases complementary to the RNA encoding the fit-i receptor. is 22. The method of claim 20, wherein said enzymatic nucleic acid molecule comprises between 14 and 24 bases complementary to the RNA encoding the fit-i receptor.

23. A method of cleaving RNA of the fit-i gene comprising the step of contacting said RNA with the enzymatic nucleic acid molecule of any one of claims 1 to 8, said method being substantially as hereinbefore described with reference to any one of Examples 3, 5, 7, 10 and 11.

24. A method for the treatment of a patient having a condition associated with the level of fit-i, wherein the patient, a tissue donor or population of corresponding cells is administered with a therapeutically effective amount of an enzymatic nucleic acid molecule of any one of claims 1 to 8, or a composition of claim 17 or claim 18. A method for the treatment of a patient having a condition associated with the level of fit-i, wherein the patient, a tissue donor or population of corresponding cells is administered with a therapeutically effective amount of an expression vector of claim 9, *or a composition of claim 19. 30 26. The method of claim 24 or claim 25, wherein said patient is a human.

27. A method for inhibiting VEGF-mediated induction of endothelial cell proliferation, said method comprising contacting endothelial cells with an enzymatic nucleic acid molecule of any one of claims 1 to 8, or a composition of claim 17 or claim 18. A02409 196

28. The method of claim 27, wherein said method is carried out in a patient in need of inhibition of VEGF-mediated induction of endothelial cell proliferation, and wherein a therapeutically effective amount of said enzymatic nucleic acid molecule or composition is administered to said patient.

29. The method of claim 28, wherein said patient is a human. A method as defined in claim 27, substantially as hereinbefore described with reference to any one of Examples 3, 5 or

31. A method for inhibiting VEGF-mediated induction of endothelial cell proliferation, said method comprising contacting endothelial cells with an expression vector of claim 9, or a composition of claim 19.

32. The method of claim 31, wherein said method is carried out in a patient in need of inhibition of VEGF-mediated induction of endothelial cell proliferation, and wherein a therapeutically effective amount of said expression vector or composition is administered to said patient.

33. The method of claim 32, wherein said patient is a human.

34. A method for inhibiting VEGF binding to its receptor, said method comprising inhibiting expression of said receptor by cleaving RNA of the fit-i gene with an enzymatic nucleic acid molecule of any one of claims 1 to 8. The method of claim 34, wherein said method is carried out in a patient in need of inhibition of VEGF binding to its receptor, and wherein a therapeutically effective amount of said enzymatic nucleic acid molecule or a composition according to So claim 17 or claim 18 is administered to said patient.

36. The method of claim 35, wherein said patient is a human. se 37. The method of claim 34, wherein said enzymatic nucleic acid molecule is encoded by an expression vector according to claim 9.

38. The method of claim 37, wherein said method is carried out in a patient in need of inhibition of VEGF binding to its receptor, and wherein a therapeutically effective amount of said expression vector or a composition according to claim 19 is *administered to said patient. see* 30 39. The method of claim 38, wherein said patient is a human.

40. A method as defined in claim 34, substantially as hereinbefore described with reference to Example 3. •go°

41. A method for inhibiting angiogenesis in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of an A02409 197 enzymatic nucleic acid molecule of any one of claims 1 to 8, or a composition according to claim 17 or claim 18.

42. A method for inhibiting angiogenesis in a patient in need thereof, said method comprising administering to said patient a therapeutically effective amount of an expression vector of claim 9, or a composition of claim 19.

43. Use of an enzymatic nucleic acid molecule of any one of claims 1 to 8, or a composition according to claim 17 or claim 18 for the manufacture of a medicament for the treatment of a patient having a condition associated with the level of fit-i.

44. Use of an expression vector of claim 9, or a composition according to claim 19 for the manufacture of a medicament for the treatment of a patient having a condition associated with the level of fit-i. Use of an enzymatic nucleic acid molecule of any one of claims 1 to 8, or a composition according to claim 17 or claim 18 for the manufacture of a medicament for inhibiting VEGF-mediated induction of endothelial cell proliferation in a patient in need is thereof.

46. Use of an expression vector of claim 9, or a composition according to claim 19 for the manufacture of a medicament for the manufacture of a medicament for inhibiting VEGF-mediated induction of endothelial cell proliferation in a patient in need thereof.

47. Use of an enzymatic nucleic acid molecule of any one of claims 1 to 8, or a composition according to claim 17 or claim 18 for the manufacture of a medicament for inhibiting VEGF binding to its receptor in a patient in need thereof. 80550S '9

48. Use of an expression vector of claim 9, or a composition according to claim SOS. 19 for the manufacture of a medicament for inhibiting VEGF binding to its receptor in a O: patient in need thereof.

49. Use of an enzymatic nucleic acid molecule of any one of claims 1 to 8, or a composition according to claim 17 or claim 18 for the manufacture of a medicament for inhibiting angiogenesis in a patient in need thereof.

50. Use of an expression vector of claim 9, or a composition according to claim S ,e 19 for the manufacture of a medicament for inhibiting angiogenesis in a patient in need 30 thereof Dated 3 November, 2003 Ribozyme Pharmaceuticals, Inc. Chiron Corporation Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON A02409