Patent Publication Number: US-2023135763-A1

Title: Products and compositions

Description:
CROSS REFERENCE TO RELATED PATENT APPLICATIONS 
     This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/318,341, filed Mar. 9, 2022, and U.S. Provisional Patent Application No. 63/222,974, filed Jul. 17, 2021, the contents of which are incorporated herein by reference in their entirety. 
    
    
     SEQUENCE LISTING 
     The instant application contains a Sequence Listing which has been submitted electronically in ST.26 (XML) format and is hereby incorporated by reference in its entirety. Said Sequence List, created on Oct. 18, 2022, is named 4690_0055i_LSL and is 5518 kilobytes in size. 
     FIELD 
     Nucleic acid products are provided that modulate, in particular interfere with or inhibit, complement factor B (CFB) gene expression. Compositions containing the nucleic acids also are provided, together with methods for their use to treat, prevent, or ameliorate complement system-associated including CFB-associated disorders such as autoimmune diseases, age-related macular degeneration (AMD), paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and C3 glomerulopathy (C3G). 
     BACKGROUND 
     The complement system is part of the innate immune system. Compared to the adaptive immune system, it is evolutionary older and conserved across most taxa. Its function includes decorating microbes of potentially pathogenic nature (a process referred to as opsonization) and target them for destruction, which is effected by a macromolecular assembly known as the membrane attachment complex (MAC). Certain components of the complement system, once activated, contribute to chemoattraction and activation of leukocytes. 
     Complement activation may be triggered by various factors which all involve presence of microbes but may also involve components of the adaptive immune system such as Ig including IgM. Three main pathways of complement activation have been recognized and are referred to as classical pathway, alternative pathway and lectin pathway. 
     In functional terms, complement activation occurs inherently at a low level (spontaneous cleavage of C3 to yield C3a and C3b) and is reinforced in the presence of microbes via an enzymatic cascade converting inactive forms of enzymes (zymogenes) into their active counterparts. The term “convertase”, such as C3 convertase, is primarily a functional term and may refer to structurally distinct complexes. One type of C3 convertases is a complex of C3b and complement factor B (CFB, Factor B). Once formed, a C3 convertase can convert large amounts of C3 into its cleavage products C3a and C3b within short amount of time. The specific C3 convertase which is a complex of C3b and Factor B has originally been described in the context of the alternative pathway, but may form also in the context of the other two pathways. Within the alternative pathway, Factor B is also a constituent of C5 convertase, a complex which converts C5, a more downstream component of the pathway, into its active form. 
     Disease 
     The complement system is generally triggered by patterns of binding sites on surfaces. These binding sites may be constituents of a microbe or pathogen, but may also be antibodies which previously bound to any target. In the latter case, the complement system acts to reinforce the adaptive immune system. As a consequence, and in case the mentioned antibodies are autoantibodies, the complement system exacerbates an undesirable auto-immune reaction. Interfering with the complement system in such a setting is a way to treat or ameliorate autoimmune diseases. Since the complement system, more specifically C1 of the classical pathway recognizes the constant portions of antibodies, interfering with the complement system opens an avenue to generally interfering with auto-immune disorder without particular limitation. Having said that, experience tells that auto-immune disorders affect skin, joints and kidneys more frequently than other organs. 
     In the other hand, complement dysfunction, in the absence of autoantibodies may be a trigger of disorders as well. Also in this context it applies that, owing to the generic mechanism of the complement system, the disease amenable to treatment by an inhibitor of the complement system, more specifically by an inhibitor of Factor B (CFB) is not particularly limited. 
     Treatment 
     Eculizumab is a humanized monoclonal antibody targeting C5 and has been approved for PNH treatment. A murine cell line is used for its production. Eculizumab shall not be used in patients with sensitivity against murine proteins. Treatment with eculizumab is very expensive and costs may exceed 600000 EUR per year and patient. 
     There therefore remains a need for therapies to treat complement-associated diseases including Factor B-associated diseases. We, therefore, aim to provide compounds, methods, and pharmaceutical compositions for the treatment of such diseases. 
     Double-stranded RNA (dsRNA) able to complementarily bind expressed mRNA has been shown to be able to block gene expression (Fire et al., 1998, Nature. 1998 Feb. 19; 391 (6669):806-1 1 and Elbashir et at., 2001 , Nature. 2001 May 24; 41 1 (6836):494-8) by a mechanism that has been termed RNA interference (RNAi). Short dsRNAs direct gene-specific, post-transcriptional silencing in many organisms, including vertebrates, and have become a useful tool for studying gene function. RNAi is mediated by the RNA-induced silencing complex (RISC), a sequence-specific, multi-component nuclease that destroys messenger RNAs homologous to the silencing trigger loaded into the RISC complex. Interfering RNA (iRNA) such as siRNAs, antisense RNA, and micro-RNA are oligonucleotides that prevent the formation of proteins by gene-silencing i.e. inhibiting gene translation of the protein through degradation of mRNA molecules. Gene-silencing agents are becoming increasingly important for therapeutic applications in medicine. 
     According to Watts and Corey in the Journal of Pathology (2012; Vol 226, p 365-379) there are algorithms that can be used to design nucleic acid silencing triggers, but all of these have severe limitations. It may take various experimental methods to identify potent siRNAs, as algorithms do not take into account factors such as tertiary structure of the target mRNA or the involvement of RNA binding proteins. Therefore, the discovery of a potent nucleic acid silencing trigger with minimal off-target effects is a complex process. For the pharmaceutical development of these highly charged molecules it is necessary that they can be synthesised economically, distributed to target tissues, enter cells and function within acceptable limits of toxicity. An aim is to, therefore, provide compounds, methods, and pharmaceutical compositions for the treatment of thromboembolic diseases as described herein, which comprise oligomeric compounds that modulate, in particular inhibit, gene expression by RNAi. 
     SUMMARY 
     Nucleic acid products are provided that modulate, in particular, interfere with or inhibit, complement factor B (CFB) gene expression, together with associated therapeutic uses. Specific oligomeric compounds and sequences are described herein. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to determine the scope of the claimed subject matter. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG.  1    shows sequence structure optimization in terms of reduction in CFB gene expression. 
         FIG.  2    shows a study design including a time line with the time points of applying the dose to the Non-Human Primates (NHP) and time points for taking samples. 
         FIG.  3   a    shows a Mean Percent of remaining factor Bb (an established read-out for CFB down-regulation and complement pathway down-regulation) levels in the plasma for a single treatment oligomeric with the inventive oligomeric constructs 106-13(4) or 13(5). 
         FIG.  3   b    shows a Mean Percent of remaining factor Bb levels in the plasma for a multiple treatment with the inventive oligomeric constructs 106-13(4) or 13(5). 
         FIG.  4   a    shows a Mean Percent of remaining factor Bb levels in the plasma for groups treated with the inventive oligomeric construct 106-13(4) in comparison with the control group. 
         FIG.  4   b    shows shows a Mean Percent of remaining factor Bb levels in the plasma for groups treated with the inventive oligomeric construct 13(5) in comparison with the control group; 
         FIG.  5    shows an overview of a study protocol in mice with humanized liver. 
         FIG.  6    shows knock-down in the mice at the mRNA level of two compounds compared to negative control after 2 and 6 weeks. 
         FIG.  7    shows amounts of CFB (“Factor B”) as well as of Factor Bb in plasma of the mice as compared to negative control after 2 and 6 weeks. 
     
    
    
     DETAILED DESCRIPTION 
     The following are non-limiting aspects. 
     Aspect 1. An oligomeric compound capable of inhibiting expression of CFB, where the compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from a CFB gene, where the first nucleobase sequence is selected from the following sequences, or a portion thereof: sequences of SEQ ID NOs 1 to 250, 751 and 752, where the portion advantageously has a length of at least 18 nucleotides. 
     Particularly advantageous embodiments relate to optimized hairpin RNAs (referred to as mxRNAs); for further details see the embodiments and their discussion further below. In addition, the antisense and sense regions disclosed herein may serve as building blocks for compounds which are directed to multiple targets. The general architecture of such compounds is described in WO 2020/065602. 
     Furthermore, and as disclosed further below, double-stranded RNAs (dsRNAs) are provided. Distinct from mxRNAs, dsRNAs lack a loop connecting antisense and sense portions and therefore comprise two strands. These two strands are not covalently connected to each other, but form a duplex region where base pairing occurs. 
     Aspect 2. A composition comprising an oligomeric compound according to aspect 1, and a physiologically acceptable excipient. 
     Aspect 3. A pharmaceutical composition comprising an oligomeric compound according to aspect 1. 
     Aspect 4. An oligomeric compound according to aspect 1, for use in human or veterinary medicine or therapy. 
     Aspect 5. An oligomeric compound according to aspect 1, for use in a method of treating a disease or disorder. 
     Aspect 6. A method of treating a disease or disorder comprising administration of an oligomeric compound according to aspect 1, to an individual in need of treatment. 
     Aspect 7. Use of an oligomeric compound according to aspect 1, for use in research as a gene function analysis tool. 
     Aspect 8. Use of an oligomeric compound according to aspect 1 in the manufacture of a medicament for a treatment of a disease or disorder. 
     Further embodiments (items) are described below by way of example only. 
     It will be understood that the benefits and advantages described herein may relate to one embodiment or may relate to several embodiments. The embodiments are not limited to those that solve any or all of the stated problems or those that have any or all of the stated benefits and advantages. 
     Features of different aspects and embodiments as described herein may be combined as appropriate, as would be apparent to a skilled person, and may be combined with any other aspects. 
     Definitions 
     Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis, and chemical analysis. Certain such techniques and procedures may be found for example in “Carbohydrate Modifications in Antisense Research” Edited by Sangvi and Cook, American Chemical Society, Washington D.C., 1994; “Remington&#39;s Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 21st edition, 2005; and “Antisense Drug Technology, Principles, Strategies, and Applications” Edited by Stanley T. Crooke, CRC Press, Boca Raton, Fla.; and Sambrook et al., “Molecular Cloning, A laboratory Manual,” 2nd Edition, Cold Spring Harbor Laboratory Press, 1989, which are hereby incorporated by reference for any purpose. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety. 
     Unless otherwise indicated, the following terms have the following meanings: 
     As used herein, “excipient” means any compound or mixture of compounds that is added to a composition as provided herein that is suitable for delivery of an oligomeric compound. 
     As used herein, “nucleoside” means a compound comprising a nucleobase moiety and a sugar moiety. Nucleosides include, but are not limited to, naturally occurring nucleosides (as found in DNA and RNA) and modified nucleosides. Nucleosides may be linked to a phosphate moiety, phosphate-linked nucleosides also being referred to as “nucleotides”. 
     As used herein, “chemical modification” or “chemically modified” means a chemical difference in a compound when compared to a naturally occurring counterpart. Chemical modifications of oligonucleotides include nucleoside modifications (including sugar moiety modifications and nucleobase modifications) and intemucleoside linkage modifications. In reference to an oligonucleotide, chemical modification does not include differences only in nucleobase sequence. 
     As used herein, “furanosyl” means a structure comprising a 5-membered ring comprising four carbon atoms and one oxygen atom. 
     As used herein, “naturally occurring sugar moiety” means a ribofuranosyl as found in naturally occurring RNA or a deoxyribofuranosyl as found in naturally occurring DNA. A “naturally occurring sugar moiety” as referred to herein is also termed as an “unmodified sugar moiety”. 
     In particular, such a “naturally occurring sugar moiety” or an “unmodified sugar moiety” as referred to herein has a —H (DNA sugar moiety) or —OH (RNA sugar moiety) at the 2′-position of the sugar moiety, especially a —H (DNA sugar moiety) at the 2′-position of the sugar moiety. 
     As used herein, “sugar moiety” means a naturally occurring sugar moiety or a modified sugar moiety of a nucleoside. As used herein, “modified sugar moiety” means a substituted sugar moiety or a sugar surrogate. 
     As used herein, “substituted sugar moiety” means a furanosyl that has been substituted. 
     Substituted sugar moieties include, but are not limited to furanosyls comprising substituents at the 2′-position, the 3′-position, the 5′-position and/or the 4′-position. Certain substituted sugar moieties are bicyclic sugar moieties. 
     As used herein, “2′-substituted sugar moiety” means a furanosyl comprising a substituent at the 2′-position other than H or OH. Unless otherwise indicated, a 2′-substituted sugar moiety is not a bicyclic sugar moiety (i.e., the 2′-substituent of a 2′-substituted sugar moiety does not form a bridge to another atom of the furanosyl ring). 
     As used herein, “MOE” means —OCH 2 CH 2 OCH 3 . 
     As used herein, “2′-F nucleoside” refers to a nucleoside comprising a sugar comprising fluorine at the 2′ position. Unless otherwise indicated, the fluorine in a 2′-F nucleoside is in the ribo position (replacing the OH of a natural ribose). Duplexes of uniformly modified 2′-fluorinated (ribo) oligonucleotides hybridized to RNA strands are not RNase H substrates while the ara analogs retain RNase H activity. 
     As used herein the term “sugar surrogate” means a structure that does not comprise a furanosyl and that is capable of replacing the naturally occurring sugar moiety of a nucleoside, such that the resulting nucleoside sub-units are capable of linking together and/or linking to other nucleosides to form an oligomeric compound which is capable of hybridizing to a complementary oligomeric compound. Such structures include rings comprising a different number of atoms than furanosyl (e.g., 4, 6, or 7-membered rings); replacement of the oxygen of a furanosyl with a non-oxygen atom (e.g., carbon, sulfur, or nitrogen); or both a change in the number of atoms and a replacement of the oxygen. Such structures may also comprise substitutions corresponding to those described for substituted sugar moieties (e.g., 6-membered carbocyclic bicyclic sugar surrogates optionally comprising additional substituents). Sugar surrogates also include more complex sugar replacements (e.g., the non-ring systems of peptide nucleic acid). Sugar surrogates include without limitation morpholinos, cyclohexenyls and cyclohexitols. 
     As used herein, “bicyclic sugar moiety” means a modified sugar moiety comprising a 4 to 7 membered ring (including but not limited to a furanosyl) comprising a bridge connecting two atoms of the 4 to 7 membered ring to form a second ring, resulting in a bicyclic structure. In certain embodiments, the 4 to 7 membered ring is a sugar ring. In certain embodiments the 4 to 7 membered ring is a furanosyl. In certain such embodiments, the bridge connects the 2′-carbon and the 4′-carbon of the furanosyl. 
     As used herein, “nucleotide” means a nucleoside further comprising a phosphate linking group. 
     As used herein, “linked nucleosides” may or may not be linked by phosphate linkages and thus includes, but is not limited to “linked nucleotides.” As used herein, “linked nucleosides” are nucleosides that are connected in a continuous sequence (i.e. no additional nucleosides are present between those that are linked). 
     As used herein, “nucleobase” means a group of atoms that can be linked to a sugar moiety to create a nucleoside that is capable of incorporation into an oligonucleotide, and where the group of atoms is capable of bonding, more specifically hydrogen bonding, with a complementary naturally occurring nucleobase of another oligonucleotide or nucleic acid. Nucleobases may be naturally occurring or may be modified. 
     As used herein the terms, “unmodified nucleobase” or “naturally occurring nucleobase” means the naturally occurring heterocyclic nucleobases of RNA or DNA: the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) (including 5-methyl C), and uracil (U). 
     As used herein, “modified nucleobase” means any nucleobase that is not a naturally occurring nucleobase. 
     As used herein, “modified nucleoside” means a nucleoside comprising at least one chemical modification compared to naturally occurring RNA or DNA nucleosides. Modified nucleosides can comprise a modified sugar moiety and/or a modified nucleobase. 
     As used herein, “bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclic sugar moiety. 
     As used herein, “locked nucleic acid nucleoside” or “LNA” means a nucleoside comprising a bicyclic sugar moiety comprising a 4′-CH 2 —O-2′bridge. 
     As used herein, “2′-substituted nucleoside” means a nucleoside comprising a substituent at the 2′-position of the sugar moiety other than H or OH. Unless otherwise indicated, a 2′-substituted nucleoside is not a bicyclic nucleoside. 
     As used herein, “deoxynucleoside” means a nucleoside comprising 2′-H furanosyl sugar moiety, as found in naturally occurring deoxyribonucleosides (DNA). In certain embodiments, a 2′-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (e.g., uracil). 
     As used herein, “oligonucleotide” means a compound comprising a plurality of linked nucleosides. In certain embodiments, an oligonucleotide comprises one or more unmodified ribonucleosides (RNA) and/or unmodified deoxyribonucleosides (DNA) and/or one or more modified nucleosides. 
     As used herein, “modified oligonucleotide” means an oligonucleotide comprising at least one modified nucleoside and/or at least one modified internucleoside linkage. 
     Advantageous modified internucleoside linkages include those which confer increased stability as compared to the naturally occurring phosphodiesters. “Stability” refers in particular to stability against hydrolysis including enzyme-catalyzed hydrolysis, enzymes including exonucleases and endonucleases. 
     Advantageously, such modified internucleoside linkages may be placed at the termini and/or the hairpin loop of single-stranded oligomeric compounds as described herein. For example, the internucleoside linkages connecting first and second nucleoside and second and third nucleoside counting from the 5′ terminus, and/or the internucleoside linkages connecting first and second nucleoside and second and third nucleoside counting from the 3′ terminus are modified. In addition, a linkage connecting the terminal nucleoside of the 3′ terminus with a ligand, such as GalNAc, may be modified. 
     As discussed above, advantageous positions are in the hairpin loop of the single-stranded oligomeric compounds. In particular, all linkages, all but one linkages or the majority of linkages in the hairpin loop are modified. As used herein, “linkages in the hairpin loop” designates the linkages between nucleosides which are not engaged in base pairing. For example, in a hairpin loop consisting of five nucleosides, there are four linkages between nucleosides which are not engaged in base pairing. “Linkages in the hairpin loop” may also extend to the linkages connecting the stem to the loop, i.e., those linkages which connect a base-paired nucleoside to a non-based paired nucleoside. Generally, there are two such positions in hairpins and mxRNAs as described herein. 
     Advantageously the modified internucleoside linkages are at both termini and in the hairpin loop. 
     As used herein, “linkage” or “linking group” means a group of atoms that link together two or more other groups of atoms. 
     As used herein “intemucleoside linkage” means a covalent linkage between adjacent nucleosides in an oligonucleotide. 
     As used herein “naturally occurring intemucleoside linkage” means a 3′ to 5′ phosphodiester linkage. As used herein, “modified internucleoside linkage” means any intemucleoside linkage other than a naturally occurring internucleoside linkage. In particular, a “modified internucleoside linkage” as referred to herein can include a modified phosphorous linking group such as a phosphorothioate or phosphorodithioate internucleoside linkage. 
     As used herein, “terminal internucleoside linkage” means the linkage between the last two nucleosides of an oligonucleotide or defined region thereof. 
     As used herein, “phosphorus linking group” means a linking group comprising a phosphorus atom and can include naturally occurring phosphorous linking groups as present in naturally occurring RNA or DNA, such as phosphodiester linking groups, or modified phosphorous linking groups that are not generally present in naturally occurring RNA or DNA, such as phosphorothioate or phosphorodithioate linking groups. Phosphorus linking groups can therefore include without limitation, phosphodiester, phosphorothioate, phosphorodithioate, phosphonate, methylphosphonate, phosphoramidate, phosphorothioamidate, thionoalkylphosphonate, phosphotriesters, thionoalkylphosphotriester and boranophosphate. 
     As used herein, “internucleoside phosphorus linking group” means a phosphorus linking group that directly links two nucleosides. 
     As used herein, “oligomeric compound” means a polymeric structure comprising two or more substructures. In certain embodiments, an oligomeric compound comprises an oligonucleotide, such as a modified oligonucletide. In certain embodiments, an oligomeric compound further comprises one or more conjugate groups and/or terminal groups and/or ligands. In certain embodiments, an oligomeric compound consists of an oligonucleotide. In certain embodiments, an oligomeric compound comprises a backbone of one or more linked monomeric sugar moieties, where each linked monomeric sugar moiety is directly or indirectly attached to a heterocyclic base moiety. In certain embodiments, oligomeric compounds may also include monomeric sugar moieties that are not linked to a heterocyclic base moiety, thereby providing abasic sites. Oligomeric compounds may be defined in terms of a nucleobase sequence only, i.e., by specifying the sequence of A, G, C, U (or T). In such a case, the structure of the sugar-phosphate backbone is not partictularly limited and may or may not comprise modified sugars and/or modified phosphates. On the other hand, oligomeric compounds may be more comprehensively defined, i.e, by specifying not only the nucleobase sequence, but also the structure of the backbone, in particular the modification status of the sugars (unmodified, 2′-OMe modified, 2′-F modified etc.) and/or of the phosphates. 
     As used herein, “terminal group” means one or more atom attached to either, or both, the 3′ end or the 5′ end of an oligonucleotide. In certain embodiments, a terminal group comprises one or more terminal group nucleosides. 
     As used herein, “conjugate” or “conjugate group” means an atom or group of atoms bound to an oligonucleotide or oligomeric compound. In certain embodiments, a conjugate group links a ligand to a modified oligonucleotide or oligomeric compound. In general, conjugate groups can modify one or more properties of the compound to which they are attached, including, but not limited to pharmacodynamic, pharmacokinetic, binding, absorption, cellular distribution, cellular uptake, charge and/or clearance properties. 
     As used herein, “conjugate linker” or “linker” in the context of a conjugate group means a portion of a conjugate group comprising any atom or group of atoms and which covalently link an oligonucleotide to another portion of the conjugate group. In certain embodiments, the point of attachment on the oligomeric compound is the 3′-oxygen atom of the 3′-hydroxyl group of the 3′ terminal nucleoside of the oligonucleotide. In certain embodiments the point of attachment on the oligomeric compound is the 5′-oxygen atom of the 5′-hydroxyl group of the 5′ terminal nucleoside of the oligonucleotide. In certain embodiments, the bond for forming attachment to the oligomeric compound is a cleavable bond. In certain such embodiments, such cleavable bond constitutes all or part of a cleavable moiety. 
     In certain embodiments, conjugate groups comprise a cleavable moiety (e.g., a cleavable bond or cleavable nucleoside) and ligand portion that can comprise one or more ligands, such as a carbohydrate cluster portion, such as an N-Acetyl-Galactosamine, also referred to as “GalNAc”, cluster portion. In certain embodiments, the carbohydrate cluster portion is identified by the number and identity of the ligand. For example, in certain embodiments, the carbohydrate cluster portion comprises 2 GalNAc groups. For example, in certain embodiments, the carbohydrate cluster portion comprises 3 GalNAc groups. In certain embodiments, the carbohydrate cluster portion comprises 4 GalNAc groups. Such ligand portions are attached to an oligomeric compound via a cleavable moiety, such as a cleavable bond or cleavable nucleoside. The ligands can be arranged in a linear or branched configuration, such as a biantennary or triantennary configurations. An example of a carbohydrate cluster has the following formula: 
     
       
         
         
             
             
         
       
     
     where in the structural formula one, two, or three phosphodiester linkages can also be substituted by phosphothionate linkages. 
     As used herein, “cleavable moiety” means a bond or group that is capable of being cleaved under physiological conditions. In certain embodiments, a cleavable moiety is cleaved inside a cell or sub-cellular compartments, such as an endosome or lysosome. In certain embodiments, a cleavable moiety is cleaved by endogenous enzymes, such as nucleases. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds. In certain embodiments, a cleavable moiety is a phosphodiester linkage. 
     As used herein, “cleavable bond” means any chemical bond capable of being broken. 
     As used herein, “carbohydrate cluster” means a compound having one or more carbohydrate residues attached to a linker group. 
     As used herein, “modified carbohydrate” means any carbohydrate having one or more chemical modifications relative to naturally occurring carbohydrates. 
     As used herein, “carbohydrate derivative” means any compound which may be synthesized using a carbohydrate as a starting material or intermediate. 
     As used herein, “carbohydrate” means a naturally occurring carbohydrate, a modified carbohydrate, or a carbohydrate derivative. A carbohydrate is a biomolecule including carbon (C), hydrogen (H) and oxygen (O) atoms. Carbohydrates can include monosaccharide, disaccharides, trisaccharides, tetrasaccharides, oligosaccharides or polysaccharides, such as one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl-Galactosamine moieties, and/or one or more mannose moieties. Advantageously the carbohydrate is N-Acetyl-Galactosamine. 
     As used herein, “strand” means an oligomeric compound comprising linked nucleosides. 
     As used herein, “single strand” or “single-stranded” means an oligomeric compound comprising linked nucleosides that are connected in a continuous sequence without a break therebetween. Such single strands may include regions of sufficient self-complementarity so as to be capable of forming a stable self-duplex in a hairpin structure. 
     As used herein, “hairpin” means a single stranded oligomeric compound that includes a duplex formed by base pairing between sequences in the strand that are self-complementary and opposite in directionality. 
     As used herein, “hairpin loop” means an unpaired loop of linked nucleosides in a hairpin that is created as a result of hybridization of the self-complementary sequences. The resulting structure looks like a loop or a U-shape. 
     In particular, short hairpin RNA, also denoted as shRNA, comprises a duplex region and a loop connecting the regions forming the duplex. The end of the duplex region which does not carry the loop may be blunt-ended or carry (a) 3′ and/or (a) 5′ overhang(s). Blunt-ended constructs are particularly advantageous. 
     As used herein, “directionality” means the end-to-end chemical orientation of an oligonucleotide based on the chemical convention of numbering of carbon atoms in the sugar moiety meaning that there will be a 5′-end defined by the 5′ carbon of the sugar moiety, and a 3′-end defined by the 3′ carbon of the sugar moiety. In a duplex or double stranded oligonucleotide, the respective strands run in opposite 5′ to 3′ directions to permit base pairing between them. 
     As used herein, “duplex”, or also abbreviated as “dup”, means two or more complementary strand regions, or strands, of an oligonucleotide or oligonucleotides, hybridized together by way of non-covalent, sequence-specific interaction therebetween. Most commonly, the hybridization in the duplex will be between nucleobases adenine (A) and thymine (T), and/or (A) adenine and uracil (U), and/or guanine (G) and cytosine (C). The duplex may be part of a single stranded structure, where self-complementarity leads to hybridization, or as a result of hybridization between respective strands in a double stranded construct. 
     As used herein, “double strand” or “double stranded” means a pair of oligomeric compounds that are hybridized to one another. In certain embodiments, a double-stranded oligomeric compound comprises a first and a second oligomeric compound. 
     As used herein, “expression” means the process by which a gene ultimately results in a protein. Expression includes, but is not limited to, transcription, post-transcriptional modification (e.g., splicing, polyadenlyation, addition of 5′-cap), and translation. 
     As used herein, “transcription” or “transcribed” refers to the first of several steps of DNA based gene expression in which a target sequence of DNA is copied into RNA (especially mRNA) by the enzyme RNA polymerase. During transcription, a DNA sequence is read by an RNA polymerase, which produces a complementary, antiparallel RNA sequence called a primary transcript. 
     As used herein, “target sequence” means a sequence to which an oligomeric compound is intended to hybridize to result in a desired activity with respect to CFB expression. Oligonucleotides have sufficient complementarity to their target sequences to allow hybridization under physiological conditions. 
     As used herein, “nucleobase complementarity” or “complementarity” when in reference to nucleobases means a nucleobase that is capable of base pairing with another nucleobase. For example, in DNA, adenine (A) is complementary to thymine (T). For example, in RNA, adenine (A) is complementary to uracil (U). In both DNA and RNA, guanine (G) is complementary to cytosine (C). In certain embodiments, complementary nucleobase means a nucleobase of an oligomeric compound that is capable of base pairing with a nucleobase of its target sequence. For example, if a nucleobase at a certain position of an oligomeric compound is capable of hydrogen bonding with a nucleobase at a certain position of a target sequence, then the position of hydrogen bonding between the oligomeric compound and the target sequence is considered to be complementary at that nucleobase pair. Nucleobases comprising certain modifications may maintain the ability to pair with a counterpart nucleobase and thus, are still capable of nucleobase complementarity. 
     As used herein, “non-complementary” in reference to nucleobases means a pair of nucleobases that do not form hydrogen bonds with one another. 
     As used herein, “complementary” in reference to oligomeric compounds (e.g., linked nucleosides, oligonucleotides) means the capacity of such oligomeric compounds or regions thereof to hybridize to a target sequence, or to a region of the oligomeric compound itself, through nucleobase complementarity. 
     Complementary oligomeric compounds need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. In certain embodiments, complementary oligomeric compounds or regions are complementary at 70% of the nucleobases (70% complementary). In certain embodiments, complementary oligomeric compounds or regions are 80%&gt; complementary. In certain embodiments, complementary oligomeric compounds or regions are 90%&gt; complementary. In certain embodiments, complementary oligomeric compounds or regions are at least 95% complementary. In certain embodiments, complementary oligomeric compounds or regions are 100% complementary. 
     As used herein, “self-complementarity” in reference to oligomeric compounds means a compound that may fold back on itself, creating a duplex as a result of nucleobase hybridization of internal complementary strand regions. Depending on how close together and/or how long the strand regions are, then the compound may form hairpin loops, junctions, bulges or internal loops. 
     As used herein, “mismatch” means a nucleobase of an oligomeric compound that is not capable of pairing with a nucleobase at a corresponding position of a target sequence, or at a corresponding position of the oligomeric compound itself when the oligomeric compound hybridizes as a result of self-complementarity, when the oligomeric compound and the target sequence and/or self-complementary regions of the oligomeric compound, are aligned. 
     As used herein, “hybridization” means the pairing of complementary oligomeric compounds (e.g., an oligomeric compound and its target sequence). While not limited to a particular mechanism, the most common mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases. 
     As used herein, “specifically hybridizes” means the ability of an oligomeric compound to hybridize to one nucleic acid site with greater affinity than it hybridizes to another nucleic acid site. 
     As used herein, “fully complementary” in reference to an oligomeric compound or region thereof means that each nucleobase of the oligomeric compound or region thereof is capable of pairing with a nucleobase of a complementary nucleic acid target sequence or a self-complementary region of the oligomeric compound. Thus, a fully complementary oligomeric compound or region thereof comprises no mismatches or unhybridized nucleobases with respect to its target sequence or a self-complementary region of the oligomeric compound. 
     As used herein, “percent complementarity” means the percentage of nucleobases of an oligomeric compound that are complementary to an equal-length portion of a target nucleic acid. Percent complementarity is calculated by dividing the number of nucleobases of the oligomeric compound that are complementary to nucleobases at corresponding positions in the target nucleic acid by the total length of the oligomeric compound. 
     As used herein, “percent identity” means the number of nucleobases in a first nucleic acid that are the same type (independent of chemical modification) as nucleobases at corresponding positions in a second nucleic acid, divided by the total number of nucleobases in the first nucleic acid. 
     As used herein, “modulation” means a change of amount or quality of a molecule, function, or activity when compared to the amount or quality of a molecule, function, or activity prior to modulation. For example, modulation includes the change, either an increase (stimulation or induction) or a decrease (inhibition or reduction) in gene expression. 
     As used herein, “type of modification” in reference to a nucleoside or a nucleoside of a “type” means the chemical modification of a nucleoside and includes modified and unmodified nucleosides. Accordingly, unless otherwise indicated, a “nucleoside having a modification of a first type” may be an unmodified nucleoside. 
     As used herein, “differently modified” mean chemical modifications or chemical substituents that are different from one another, including absence of modifications. Thus, for example, a MOE nucleoside and an unmodified naturally occurring RNA nucleoside are “differently modified,” even though the naturally occurring nucleoside is unmodified. Likewise, DNA and RNA oligonucleotides are “differently modified,” even though both are naturally-occurring unmodified nucleosides. Nucleosides that are the same but for comprising different nucleobases are not differently modified. For example, a nucleoside comprising a 2′-OMe modified sugar moiety and an unmodified adenine nucleobase and a nucleoside comprising a 2′-OMe modified sugar moiety and an unmodified thymine nucleobase are not differently modified. 
     As used herein, “the same type of modifications” refers to modifications that are the same as one another, including absence of modifications. Thus, for example, two unmodified RNA nucleosides have “the same type of modification,” even though the RNA nucleosides are unmodified. Such nucleosides having the same type modification may comprise different nucleobases. 
     As used herein, “region” or “regions”, or “portion” or “portions”, mean a plurality of linked nucleosides that have a function or character as defined herein, in particular with reference to the claims and definitions as provided herein. Typically such regions or portions comprise at least 10, at least 11, at least 12 or at least 13 linked nucleosides. For example, such regions can comprise 13 to 20 linked nucleosides, such as 13 to 16 or 18 to 20 linked nucleosides. 
     Typically a first region as defined herein consists essentially of 18 to 20 nucleosides and a second region as defined herein consists essentially of 13 to 16 linked nucleosides. As used herein, “pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to an animal. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile saline. In certain embodiments, such sterile saline is pharmaceutical grade saline. 
     As used herein, “substituent” and “substituent group,” means an atom or group that replaces the atom or group of a named parent compound. For example a substituent of a modified nucleoside is any atom or group that differs from the atom or group found in a naturally occurring nucleoside (e.g., a modified 2′-substituent is any atom or group at the 2′-position of a nucleoside other than H or OH). Substituent groups can be protected or unprotected. In certain embodiments, compounds of the present disclosure have substituents at one or at more than one position of the parent compound. Substituents may also be further substituted with other substituent groups and may be attached directly or via a linking group such as oxygen or an alkyl or hydrocarbyl group to a parent compound. 
     Such substituents can be present as the modification on the sugar moiety, in particular a substituent present at the 2′-position of the sugar moiety. Unless otherwise indicated, groups amenable for use as substituents include without limitation, one or more of halo, hydroxyl, alkyl, alkenyl, alkynyl, acyl, carboxyl, alkoxy, alkoxyalkylene and amino substituents. Certain substituents as described herein can represent modifications directly attached to a ring of a sugar moiety (such as a halo, such as fluoro, directly attached to a sugar ring), or a modification indirectly linked to a ring of a sugar moiety by way of an oxygen linking atom that itself is directly linked to the sugar moiety (such as an alkoxyalkylene, such as methoxyethylene, linked to an oxygen atom, overall providing an MOE substituent as described herein attached to the 2′-position of the sugar moiety). 
     As used herein, “alkyl,” as used herein, means a saturated straight or branched monovalent C 1-6  hydrocarbon radical. Methyl is advantageously the alkyl employed as a substituent at the 2′-position of the sugar moiety. The alkyl group typically attaches to an oxygen linking atom at the 2′position of the sugar, therefore, overall providing a —Oalkyl substituent, such as an —OCH 3  substituent, on a sugar moiety of an oligomeric compound as described herein. This will be well understood be a person skilled in the art. 
     As used herein, “alkylene” means a saturated straight or branched divalent hydrocarbon radical of the general formula —C n H 2n — where n is 1-6. Methylene or ethylene are advantageous alkylenes. 
     As used herein, “alkenyl” means a straight or branched unsaturated monovalent C 2-6  hydrocarbon radical, with ethenyl or propenyl being specific alkenyls as a substituent at the 2′-position of the sugar moiety. As will be well understood in the art, the degree of unsaturation that is present in an alkenyl radical is the presence of at least one carbon to carbon double bond. 
     The alkenyl group typically attaches to an oxygen linking atom at the 2′-position of the sugar, therefore, overall providing a —Oalkenyl substituent, such as an —OCH 2 CH═CH 2  substituent, on a sugar moiety of an oligomeric compound as described herein. This will be well understood be a person skilled in the art. 
     As used herein, “alkynyl” means a straight or branched unsaturated C 2-6  hydrocarbon radical, with ethynyl being an example of a substituent at the 2′-position of the sugar moiety. As will be well understood in the art, the degree of unsaturation that is present in an alkynyl radical is the presence of at least one carbon to carbon triple bond. The alkynyl group typically attaches to an oxygen linking atom at the 2′-position of the sugar, therefore, overall providing a —Oalkynyl substituent on a sugar moiety of an oligomeric compound as described herein. This will be well understood be a person skilled in the art. 
     As used herein, “carboxyl” is a radical having a general formula —CO 2 H. 
     As used herein, “acyl” means a radical formed by removal of a hydroxyl group from a carboxyl radical as defined herein and has the general Formula —C(O)—X where X is typically C 1-6  alkyl. 
     As used herein, “alkoxy” means a radical formed between an alkyl group, such as a C 1-6  alkyl group, and an oxygen atom where the oxygen atom is used to attach the alkoxy group either to a parent molecule (such as at the 2′-position of a sugar moiety), or to another group such as an alkylene group as defined herein. Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy. Alkoxy groups as used herein may optionally include further substituent groups. 
     As used herein, alkoxyalkylene means an alkoxy group as defined herein that is attached to an alkylene group also as defined herein, and where the oxygen atom of the alkoxy group attaches to the alkylene group and the alkylene attaches to a parent molecule. The alkylene group typically attaches to an oxygen linking atom at the 2′-position of the sugar, therefore, overall providing a —Oalkylenealkoxy substituent, such as an —OCH 2 CH 2 OCH 3  substituent, on a sugar moiety of an oligomeric compound as described herein. This will be well understood by a person skilled in the art and is generally referred to as an MOE substituent as defined herein and as known in the art. 
     As used herein, “amino” includes primary, secondary and tertiary amino groups. 
     As used herein, “halo” and “halogen,” mean an atom selected from fluorine, chlorine, bromine and iodine. 
     As used herein, the term “mxRNA” is in particular understood as defined in WO 2020/044186 A2 which is incorporated by reference herein in its entirety. 
     As used herein, the term “factor Bb” denotes the corresponding and commonly known protein which binds to C3b within the C3 convertase within complement activation. Factor Bb is an active subunit of CFB and can be produced by a cleavage of CFB into factors Ba and Bb due to factor D, for example in the alternative pathway of the complement activation, after CFB is bound to C3b. The factor Bb level can, such as in the examples provided below, be used as an indicator for the success of a silencing of CFB expression. 
     It will also be understood that oligomeric compounds as described herein may have one or more non-hybridizing nucleosides at one or both ends of one or both strands (overhangs) and/or one or more internal non-hybridizing nucleosides (mismatches) provided there is sufficient complementarity to maintain hybridization under physiologically relevant conditions. 
     Alternatively, oligomeric compounds as described herein may be blunt ended at at least one end. 
     The term “comprising” is used herein to mean including the method steps or elements identified, but that such steps or elements do not comprise an exclusive list and as such there may be present additional steps or elements. 
     Further, to the extent that the term “includes” is used in either the detailed description or the claims, such term is intended to be inclusive in a manner similar to the term “comprising” as “comprising” is interpreted when employed as a transitional word in a claim. 
     The following non-limiting embodiments (items) are provided: 
     1. An oligomeric compound capable of inhibiting expression of complement factor B (CFB), where the compound comprises at least a first region of linked nucleosides having at least a first nucleobase sequence that is at least partially complementary to at least a portion of RNA transcribed from an CFB gene, where the first nucleobase sequence is selected from the following sequences, or a portion thereof: sequences of Table la (SEQ ID NOs: 1 to 250, 751 and 752), where the portion advantageously has a length of at least 18 nucleotides. 
     The first region is also referred to as antisense region or guide region, and the second region is also referred to as sense region or passenger region. As disclosed in specific embodiments below, the two regions may be located on the same strand, advantageously in an adjacent manner. This gives rise to hairpin molecules, also referred to as mxRNAs. On the other hand, the two regions may be located on separate strands which gives rise to double-stranded RNAs (dsRNAs), where advantageously each strand consists of the respective region. 
     Morever, the regions may serve as building blocks for muRNAs (see above). In other words, the first and the second region as defined herein may be used, in accordance with the following definition of muRNAs, as first and third regions, respectively: 
     A nucleic acid construct (muRNA) comprising at least: 
     (a) a first nucleic acid portion that is at least partially complementary to at least a first portion of an RNA which is transcribed from a CFB gene; 
     (b) a second nucleic acid portion that is at least partially complementary to at least a second portion of an RNA which is transcribed from another gene; 
     (c) a third nucleic acid portion that is at least partially complementary to the first nucleic acid portion of (a), so as to form a first nucleic acid duplex region therewith; 
     (d) a fourth nucleic acid portion that is at least partially complementary to the second nucleic acid portion of (b), so as to form a second nucleic acid duplex region therewith. 
     Specific embodiments of and further aspects relating to muRNAs are disclosed in WO 2020/065602. 
     Specific nucleobase sequences are those of SEQ ID NOs: 751 and 752. 
     2. The oligomeric compound according to item 1, which further comprises at least a second region of linked nucleosides having at least a second nucleobase sequence that is at least partially complementary to the first nucleobase sequence and is selected from the following sequences, or a portion thereof: sequences of Table lb (SEQ ID NOs: 251 to 500, 753 and 754), where the portion advantageously has a length of at least 8, 9, 10 or 11 nucleotides. 
     Specific nucleobase sequences are those of SEQ ID NOs: 753 and 754. 
     3. The oligomeric compound according to item 1 or 2, where the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs: 94, 247, 13, 106, 28, 135, 132, 32, 83, 102, 62, 241, 9, 54, 143, 103, 128, 53, 150, 82, 36, 25, 71, 17, 5, 141, 90, 127, 75, 95, 751, and 752. 
     4. The oligomeric compound according to item 3, where the second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs: 344, 497, 263, 356, 278, 385, 382, 282, 333, 352, 312, 491, 259, 304, 393, 353, 378, 303, 400, 332, 286, 275, 321, 267, 255, 391, 340, 377, 325, 345, 753 and 754. 
     5. The oligomeric compound according to any of items 1 to 4, where the first nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs: 13, 53, 62, 83, 102, 106, 135, 751, and 752. 
     6. The oligomeric compound according to item 5, where the second nucleobase sequence is selected from the following sequences, or a portion thereof: SEQ ID NOs: 263, 303, 312, 333, 352, 356, 385, 753 and 754. 
     7. The oligomeric compound according to any of items 1 to 6, where the first region of linked nucleosides consists essentially of 18 to 35, 18 to 20, 18 or 19, or 19 linked nucleosides. 
     8. The oligomeric compound according to any of items 2 to 7, where the second region of linked nucleosides consists essentially of 10 to 35, 10 to 20, 10 to 16, or 10 to 15 linked nucleosides, such as 11, 12, 13 or 14 linked nucleosides, 14 being especially advantageous. 
     9. The oligomeric compound according to any of items 2 to 8, which comprises at least one complementary duplex region that comprises at least a portion of the first nucleoside region directly or indirectly linked to at least a portion of the second nucleoside region, where advantageously the duplex region has a length of 10 to 19, 12 to 19, 12 to 15 base pairs, 13 or 14 base pairs, or 14 base pairs, where optionally there is one mismatch within the duplex region. 
     10. The oligomeric compound according to item 9, where each of the first and second nucleoside regions has a 5′ to 3′ directionality thereby defining 5′ and 3′ regions respectively thereof. 
     11. The oligomeric compound according to item 10, where the 5′ region of the first nucleoside region is directly or indirectly linked to the 3′ region of the second nucleoside region, for example by complementary base pairing, where advantageously the 5′ terminal nucleoside of the first nucleoside region base pairs with the 3′ terminal nucleoside of the second nucleoside region. 
     12. The oligomeric compound according to item 11 or 13, where the 3′ region of the first nucleoside region is directly or indirectly linked to the 5′ region of the second nucleoside region, where advantageously the first nucleoside region is directly and covalently linked to the second nucleoside region such as by a phosphate, a phosphorothioate, or a phosphorodithoate. This amounts to the formation of a single oligonucleotide comprising or consisting of the two regions being directly fused to each other. Owing to the base pairing as defined in the previous embodiment, such oligonucleotide will assume a hairpin configuration. Optimized hairpins, especially in terms of size, are the subject of further embodiments below. 
     13. The oligomeric compound according to any of items 1 to 12, which further comprises one or more ligands. 
     14. The oligomeric compound according to item 13, where the one or more ligands are conjugated to the second nucleoside region and/or the first nucleoside region. 
     15. The oligomeric compound according to item 14, as dependent on item 10, where the one or more ligands are conjugated at the 3′ region, advantageously to the 3′ end of the second nucleoside region and/or of the first nucleoside region, and/or to the 5′ end of the second nucleoside region. 
     16. The oligomeric compound according to any of items 13 to 15, where the one or more ligands are any cell directing moiety, such as lipids, carbohydrates, aptamers, vitamins and/or peptides that bind cellular membrane or a specific target on cellular surface. 
     17. The oligomeric compound according to item 16, where the one or more ligands comprise one or more carbohydrates. 
     18. The oligomeric compound according to item 17, where the one or more carbohydrates can be a monosaccharide, disaccharide, trisaccharide, tetrasaccharide, oligosaccharide or polysaccharide. 
     19. The oligomeric compound according to item 18, where the one or more carbohydrates comprise or consist of one or more hexose moieties. 
     20. The oligomeric compound according to item 19, where the one or more hexose moieties are one or more galactose moieties, one or more lactose moieties, one or more N-Acetyl-Galactosamine moieties, and/or one or more mannose moieties. 
     21. The oligomeric compound according to item 20, where the one or more carbohydrates comprise one or more N-Acetyl-Galactosamine moieties. 
     22. The oligomeric compound according to item 21, which comprises two or three N-Acetyl-Galactosamine moieties, advantageously three. 
     23. The oligomeric compound according to any of items 13 to 22, where the one or more ligands are attached to the oligomeric compound, advantageously to the second nucleoside region thereof, in a linear configuration, or in a branched configuration. 
     A specific ligand is the following, also referred to as “toothbrush”: 
     
       
         
         
             
             
         
       
     
     24. The oligomeric compound according to item 23, where the one or more ligands are attached to the oligomeric compound as a biantennary or triantennary configuration. 
     25. The oligomeric compound according to any one of item 1 to 24, where the compound consists of the first region of linked nucleosides and the second region of linked nucleosides. Each of the regions may constitute a separate strand, thereby giving rise to a double-stranded RNA (dsRNA). Particularly advantageous dsRNAs are those with a length of the first strand of 19 nucleosides and a length of the second region of 14 or 15, advantageously 14 nucleosides. When used for defining the length of a region or strand, the terms “nucleoside” and “nucleotide” (sometimes abbreviated “nt”) are used equivalently. 
     In the alternative, and as stated above, the two regions may be fused together, giving rise to a hairpin. 
     26. The oligomeric compound according to any one of items 1 to 24, where there is an intervening third region of linked nucleosides between the first and the second region. 
     27. The oligomeric compound according to item 26, where the oligomeric compound comprises or consists of a single strand comprising or consisting of the first, the third, and the second nucleoside regions, where the single strand dimerises whereby at least a portion of the first nucleoside region is directly or indirectly linked to at least a portion of the second nucleoside region so as to form the at least partially complementary duplex region. 
     In other words, the oligomeric compound comprises a single strand comprising the first and second nucleoside regions, where at least a portion of the first nucleoside region is directly or indirectly linked to at least a portion of the second nucleoside region so as to form the at least partially complementary duplex region. As noted above, the third region is optional. 
     28. The oligomeric compound according to any one of item 9 to 25, where the oligomeric compound comprises or consists of a single strand comprising or consisting of the first and second nucleoside regions, where the single strand dimerises whereby at least a portion of the first nucleoside region is directly or indirectly linked to at least a portion of the second nucleoside region so as to form the at least partially complementary duplex region. 
     29. The oligomeric compound according to item 28, where the first and the second nucleoside regions are directly adjacent on the single strand. 
     30. The oligomeric compound according to item 28 or 29, where the first nucleoside region has a greater number of linked nucleosides compared to the second nucleoside region. 
     31. The oligomeric compound of item 29, whereby the additional number of linked nucleosides of the first nucleoside region form a hairpin loop linking the first and second nucleoside regions. 
     Such compounds are also referred to as hairpins or mxRNAs herein. Owing to the second region being shorter as compared to the first region, the compound is optimized in terms of size (or miniaturized) as compared to a conventional siRNA which has two regions of comparable length. 
     Advantageously, the loop has 4 or 5 linked nucleosides. Particularly advantageous is a length of the first region of 19 nucleosides, of the second region of 14 nucleotides, and of the hairpin loop of 5 nucleotides, where the 5 nucleotides in the hairpin are the 5 3′-terminal nucleosides of the first region. Such a molecular architecture of a hairpin or mxRNA is also designated “14-5-14” herein. 
     32. The oligomeric compound according to any one of items 27 to 31, where the single strand has a nucleobase sequence selected from SEQ ID NOs: 751 and 752 and, where advantageously the strand has an additional nucleobase sequence selected from SEQ ID Nos: 753 and 754. 
     33. The oligomeric compound according to item 32, where the single strand is selected from Table 3, in particular from sequence “13(5) a +s” and “106-13(4) as +s”, or from Table 4. 
     34. The oligomeric compound according to item 31, as dependent on item 10, whereby the hairpin loop is present at the 3′ region of the first nucleoside region, where optionally one, two or more 3′ terminal nucleotides, to the extent the nucleobases of the one, two or more 3′ terminal nucleotides permit, fold back and form or contribute to the second nucleoside region. 
     This is a structural design also referred to as “spill-over”. It is only possible in those cases where there is self-complementarity between the nucleobases at the 3′-terminal end of the region of the guide sequence comprised in the duplex and the very 3′-terminal nucleobases of the same guide sequence. For example, this could implemented as a 13-5-13 design, thereby allowing for further miniaturization. The first “13” refers to the region of the guide sequence involved in the duplex, 5 is the length of the loop which is also formed by the guide sequence, and the second 13 refers to the second region of the duplex and is formed by one nucleobase of the guide sequence and 12 nucleobases of the passenger region in 5′ to 3′ direction. As such, a length of the guide sequence of 19 nucleotides is maintained, but the passenger sequence is shortened to 12 nucleotides. 
     A further example is a 13-4-13 design which is implemented by construct 106-13(4) as discussed in more detail below. 
     35. The oligomeric compound of item 26 or 27, where the third nucleoside region and optionally a 3′-terminal portion, advantageously consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linked nucleosides, of the first nucleoside region and/or a 5′-terminal portion, advantageously consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 linked nucleosides, of the second nucleoside region form a hairpin loop. 
     36. The oligomeric compound according to any one of items 29 to 31, where the hairpin loop comprises 4 to 10, advantageously 4 or 5 linked nucleosides. 
     37. The oligomeric compound according to any one of items 29 to 34, where the oligomeric compound has or comprises the nucleobase sequence of any one of the sequences shown in Table 2 (SEQ ID NOs: 501 to 750, 755 or 756). 
     38. The oligomeric compound according to any of items 1 to 37, which comprises internucleoside linkages and where at least one internucleoside linkage is a modified internucleoside linkage. 
     39. The oligomeric compound according to item 38, where the modified internucleoside linkage is a phosphorothioate or phosphorodithioate internucleoside linkage. 
     Specific modified internucleoside linkages are the subject of the specific embodiments which follow. Certain modified internucleoside linkages are known in the art and described in, for example, Hu et al., Signal Transduction and Targeted Therapy (2020)5:101. 
     40. The oligomeric compound according to item 39, which comprises 1 to 15 phosphorothioate or phosphorodithioate internucleoside linkages. 
     41. The oligomeric compound according to item 40, which comprises 7, 8, 9 or 10 phosphorothioate or phosphorodithioate internucleoside linkages. 
     42. The oligomeric compound according to any of items 39 to 41, as dependent on item 10, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5′ region of the first nucleoside region. 
     43. The oligomeric compound according to any of items 39 to 42, as dependent on item 10, which comprises one or more phosphorothioate or phosphorodithioate internucleoside linkages at the 5′ region of the second nucleoside region. 
     44. The oligomeric compound according to any of items 39 to 43, as dependent on any one of items 31 to 33, which comprises phosphorothioate or phosphorodithioate internucleoside linkages between at least two, at least three, at least four, at least five, adjacent nucleosides of the hairpin loop, dependent on the number of nucleotides present in the hairpin loop. 
     45. The oligomeric compound according to item 44, which comprises a phosphorothioate or phosphorodithioate internucleoside linkage between each adjacent nucleoside that is present in the hairpin loop. 
     46. The oligomeric compound according to any of items 1 to 45, where at least one nucleoside comprises a modified sugar. 
     Specific modified sugars are subject of the specific embodiments which follow. Certain modified sugars are known in the art and described in, for example, Hu et al., Signal Transduction and Targeted Therapy (2020)5:101. 
     47. The oligomeric compound according to item 46, where the modified sugar is selected from 2′ modified sugars, a conformationally restricted nucleotide (CRN) sugar such as locked nucleic acid (LNA) sugar, (S)-constrained ethyl bicyclic nucleic acid, and constrained ethyl (cEt) sugar, tricyclo-DNA, morpholino, unlocked nucleic acid (UNA) sugar, glycol nucleic acid (GNA), D-hexitol nucleic acid (HNA), and cyclohexene nucleic acid (CeNA). 
     48. The oligomeric compound according to item 47, where the 2′ modified sugar is selected from 2′-O-alkyl modified sugar, 2′-O-methyl modified sugar, 2′-O-methoxyethyl modified sugar, 2′-O-allyl modified sugar, 2′-C-allyl modified sugar, 2′-deoxy modified sugar such as 2′-deoxy ribose, 2′-F modified sugar, 2′-arabino-fluoro modified sugar, 2′-O-benzyl modified sugar, and 2′-O-methyl-4-pyridine modified sugar. 
     49. The oligomeric compound according to item 48, where at least one modified sugar is a 2′-O-methyl modified sugar. 
     50. The oligomeric compound according to item 48 or 49, where at least one modified sugar is a 2′-F modified sugar and, optionally, at most 5 sugars are 2′-F modified sugars. 
     51. The oligomeric compound of item 49 or 50, where the sugar is ribose. 
     52. The oligomeric compound according to any of items 49 to 51, as dependent on item 10, where sugars of the nucleosides at any of positions 2 and 14 downstream from the first nucleoside of the 5′ region of the first nucleoside region, do not contain 2′-O-methyl modifications. 
     53. The oligomeric compound according to any of items 49 to 52, as dependent on item 10, where sugars of the nucleosides of the second nucleoside region, that correspond in position to any of the nucleosides of the first nucleoside region at any of positions 9 to 11 downstream from the first nucleotide of the 5′ region of the first nucleoside region, do not contain 2′ methyl modifications. Positions 9 to 11 may contain 2, 1 or 0 2′-0-methyl substitutions. 
     54. The oligomeric compound of any one of items 49 to 53, where the 3′ terminal position of the second nucleoside region does not contain a 2′-0-methyl modification. 
     55. The oligomeric compound according to item 53 or 54, where sugars of the nucleosides at any of positions 2 and 14 downstream from the first nucleoside of the 5′ region of the first nucleoside region, contain 2′-F modifications. 
     56. The oligomeric compound according to any of items 53 to 55, where sugars of the nucleosides of the second nucleoside region, that correspond in position to any of the nucleosides of the first nucleoside region at any of positions 9 to 11 downstream from the first nucleoside of the 5′ region of the first nucleoside region, contain 2′-F modifications. 
     57. The oligomeric compound of item 55 or 56, where the 3′ terminal position of the second nucleoside region contains a 2′-F modification. 
     58. The oligomeric compound according to any of items 53 to 57, as dependent on item 10, where one or more of the odd numbered nucleosides starting from the 5′ region of the first nucleoside region are modified, and/or where one or more of the even numbered nucleotides starting from the 5′ region of the first nucleoside region are modified, where typically the modification of the even numbered nucleotides is a second modification that is different from the modification of odd numbered nucleotides. 
     59. The oligomeric compound according to item 58, where one or more of the odd numbered nucleosides starting from the 3′ region of the second nucleoside region are modified by a modification that is different from the modification of odd numbered nucleosides of the first nucleoside region. 
     60. The oligomeric compound according to item 58 or 59, where one or more of the even numbered nucleosides starting from the 3′ region of the second nucleoside region are modified by a modification that is different from the modification of even numbered nucleosides of the first nucleoside region according to claim  52 . 
     61. The oligomeric compound according to any of items 58 to 60, where at least one or more of the modified even numbered nucleosides of the first nucleoside region is adjacent to at least one or more of the differently modified odd numbered nucleosides of the first nucleoside region. 
     62. The oligomeric compound according to any of items 58 to 61, where at least one or more of the modified even numbered nucleosides of the second nucleoside region is adjacent to at least one or more of the differently modified odd numbered nucleosides of the second nucleoside region. 
     63. The oligomeric compound according to any of items 58 to 62, where sugars of one or more of the odd numbered nucleosides starting from the 5′ region of the first nucleoside region are 2′-0-methyl modified sugars. 
     64. The oligomeric compound according to any of items 58 to 63, where one or more of the even numbered nucleosides starting from the 5′ region of the first nucleoside region are 2′-F modified sugars. 
     65. The oligomeric compound according to any of items 58 to 64, where sugars of one or more of the odd numbered nucleosides starting from the 3′ region of the second nucleoside region are 2′-F modified sugars. 
     66. The oligomeric compound according to any of items 58 to 65, where one or more of the even numbered nucleosides starting from the 3′ region of the second nucleoside region are 2′-O-methyl modified sugars. 
     67. The oligomeric compound according to any of items 46 to 66, where sugars of a plurality of adjacent nucleosides of the first nucleoside region are modified by a common modification. 
     68. The oligomeric compound according to any of items 46 to 67, where sugars of a plurality of adjacent nucleosides of the second nucleoside region are modified by a common modification. 
     69. The oligomeric compound according to any of items 58 to 68, as dependent on any one of claims  30  to  33 , where sugars of a plurality of adjacent nucleosides of the hairpin loop are modified by a common modification. 
     70. The oligomeric compound according to any of items 67 to 69, where the common modification is a 2′-F modified sugar. 
     71. The oligomeric compound according to any of items 67 to 69, where the common modification is a 2′-0-methyl modified sugar. 
     72. The oligomeric compound according to item 71, where the plurality of adjacent 2′ methyl modified sugars are present in at least eight adjacent nucleosides of the first and/or second nucleoside regions. 
     73. The oligomeric compound according to item 71, where the plurality of adjacent 2′ methyl modified sugars are present in three or four adjacent nucleosides of the hairpin loop. 
     74. The oligomeric compound according to item 46, as dependent on any one of claims  30  to  33 , where the hairpin loop comprises at least one nucleoside having a modified sugar. 
     75. The oligomeric compound according to item 74, where the at least one nucleoside is adjacent a nucleoside with a differently modified sugar. 
     76. The oligomeric compound according to item 75, where the modified sugar is a 2′-O-methyl modified sugar, and the differently modifies sugar is a 2′-F modified sugar. 
     77. The oligomeric compound according to any of items 1 to 76, which comprises one or more nucleosides having an un-modified sugar moiety. 
     78. The oligomeric compound according to item 77, where the unmodified sugar is present in the 5′ region of the second nucleoside region. 
     79. The oligomeric compound according to item 77 or 78, as dependent on any one of items 31 to 36, where the unmodified sugar is present in the hairpin loop. 
     80. The oligomeric compound according to any of items 1 to 79, where one or more nucleosides of the first nucleoside region and/or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 3′ carbon of its sugar and the 3′ carbon of the sugar of the adjacent nucleoside, and/or one or more nucleosides of the first nucleoside region and/or the second nucleoside region is an inverted nucleoside and is attached to an adjacent nucleoside via the 5′ carbon of its sugar and the 5′ carbon of the sugar of the adjacent nucleoside. 
     81. The oligomeric compound according to any of items 1 to 80, which is blunt ended. 
     82. The oligomeric compound according to any of items 1 to 80, where either the first or second nucleoside region has an overhang. 
     83. The oligomeric compound according to any one of items 37 to 82, where the oligomeric compound is selected from the compounds set forth in Table 3. 
     84. A composition comprising an oligomeric compound according to any of items 1 to 80, and a physiologically acceptable excipient. 
     85. A pharmaceutical composition comprising an oligomeric compound according to any of items 1 to 83. 
     86. The pharmaceutical composition of item 85, further comprising a pharmaceutically acceptable excipient, diluent, antioxidant, and/or preservative. 
     87. The pharmaceutical composition of item 85 or 86, where the oligomeric compound is the only pharmaceutically active agent. 
     88. The pharmaceutical composition of item 85 or 86, where the pharmaceutical composition furthermore comprises one or more further pharmaceutically active agents. 
     89. The pharmaceutical composition of item 88, where the further pharmaceutically active agent(s) is/are (an) agent(s) which modulate(s) the innate and/or the adaptive immune system, for example a further oligomeric compound which is directed to an immune system target different from CFB, such as Interleukin-6; agents lowering the expression or level of Interleukin-6; or an agent such as an antibody targeting a complement component, such as Eculizumab. 
     90. The pharmaceutical composition of item 88 or 89, where the oligomeric compound and the further pharmaceutically active agent(s) are to be administered concomitantly or in any order. 
     91. An oligomeric compound according to any of items 1 to 83, for use in human or veterinary medicine or therapy. 
     92. An oligomeric compound according to any of items 1 to 83, for use in a method of treating, ameliorating and/or preventing a disease or disorder. 
     93. The compound for use of item 92, where the disease or disorder is a complement component-associated disease or disorder or a disease or disorder requiring reduction of CFB expression levels. 
     94. The compound for use of item 93, where the disease or disorder is selected from autoimmune disease, complement system dysfunction including aberrant upregulation of complement components such as CFB, age-related macular degeneration (AMD) including dry AMD and geographic atrophy, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), C3 glomerulopathy (C3G), Ig-mediated kidney pathologies such as IgA nephropathy and primary membranous nephropathy, asthma, rheumatic disease, rheumatoid arthritis, systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibody (ANCA) vasculitis, antiphospholipid antibody syndrome (APS), glomerulonephritis, psoriasis, dermatomyositis bullous pemphigoid, Shiga toxin  E. coli -related hemolytic uremic syndrome, myasthenia gravis (MG), neuromyelistis optica (NMO), dense deposit disease, C3 neuropathy, cold agglutinin disease, humoral and vascular transplant rejection, graft dysfunction, myocardial infarction, sensitization towards a transplant, and sepsis. 
     95. The compound for use of item 93 or 94, where the disease of disorder is selected from age-related macular degeneration (AMD) including dry AMD and geographic atrophy, paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and C3 glomerulopathy (C3G). 
     96. A method of treating a disease or disorder comprising administration of an oligomeric compound according to any of items 1 to 83, to an individual in need of treatment. 
     97. The method according to item 96, where the oligomeric compound is administered subcutaneously or intravenously to the individual. 
     98. Use of an oligomeric compound according to any of items 1 to 83, for use in research as a gene function analysis tool. 
     99. Use of an oligomeric compound according to any of items 1 to 83 in the manufacture of a medicament for a treatment of a disease or disorder. The diseases and disorders may be the same as set forth under item 91 above. 
     Effects Achieved by the Oligomeric Compounds 
     The oligomeric compounds described herein cause a significant reduction of gene expression of complement factor B, e.g. in vitro, as e.g. shown in the examples disclosed herein. In addition, a significant reduction of the Bb levels in plasma, e.g. of non-human primates such as shown in the examples, can be achieved by using the oligomeric constructs as described herein indicating the success of RNAi in mammals. In particular, these effects can last over an extended time period, such as 13 weeks, e.g. in non-human primates. Particularly, CFB levels, as determined via its cleavage product Bb, can be reduced to a large extent, such as by up to 74% by using the inventive oligormeric constructs. 
     Furthermore, it was surprisingly found that, in certain embodiments, the mentioned effects are achieved by using oligomeric compounds as described herein in the form of shRNA constructs having a reduced length of e.g. 30 or 33 nucleosides compared to conventional shRNA molecules having greater lengths. This can e.g. make a synthesis of shRNA molecules more efficient, because less units are needed. 
     The aforementioned effects can be achieved by using a dosage of the inventive oligomeric compounds of about 1 mg/kg body weight to about 10 or more mg/kg body weight in mammals, in particular with respect to, but not limited thereto, non-human primates such as shown in the examples herein. 
     In particular, the aforementioned effects were obtained by one or more than one, e.g. three doses, using a dosage of about 1 to about 3 or more mg/kg body weight in mammals, in particular with respect to non-human primates such as shown in the examples herein. 
     It has also been surprisingly found that, in certain embodiments, the aforementioned beneficial effects can be achieved by using oligomeric compounds as described herein in the form of shRNA constructs having a reduced number of fluorine substitutions, such as five fluorine substitutions in total, on the respective 2′ positions of their ribose units compared to conventional shRNA molecules. 
     For certain oligomeric compounds as described herein, being in the form of shRNA constructs, it was surprisingly found out that the aforementioned effects can be achieved by using short sense strands within the shRNA optionally having a length of 11 or 14 nucleosides which is shorter than the length of the sense strands in conventional shRNA molecules. 
     Constructs of the Inventive Oligomeric Compounds 
     The following Tables show nucleobase sequences of antisense and sense strands of oligomeric compounds as described herein as well as of nucleobase sequences of single-stranded oligomeric compounds, and definitions of modified oligomeric compounds (the notation includes nucleobase sequence, sugar modifications, and, where applicable, modified phosphates). 
     The notation used is common in the art and as the following meaning: 
     A represents adenine; 
     U represents uracil; 
     C represents cytosine; 
     G represents guanine. 
     P represents a terminal phosphate group which is advantageous but not indispensable; 
     m represents a methyl modification at the 2′ position of the sugar of the underlying nucleoside; 
     f represents a fluoro modification at the 2′ position of the sugar of the underlying nucleoside. 
     r indicates an unmodified (2′-OH) ribonucleotide; 
     (ps) or # represents a phosphorothioate inter-nucleoside linkage; 
     i represents an inverted inter-nucleoside linkage, which can be either 3′-3′, or 5′-5′; 
     vp represents vinyl phosphonate; 
     mvp represents methyl vinyl phosphonate; 
     3×GalNAc represents a trivalent GalNAc. 
     Notation used for and Features of Specific Constructs 
     Furthermore when a notation like “13(5)” is used for describing the sequence of one of the inventive constructs, the number “13” designates the sequence based on the antisense sequence of SEQ ID NO:13, e.g. comprising a portion of 18 nucleotides thereof in accordance with the first aspect, suitable for RNAi with CFB, where the number in the round brackets, i.e. 5 in the present case, designates the number of nucleosides present in the hairpin loop of the shRNA. In the particular case of 13(5), the 5′-terminal A of SEQ ID NO: 13 has been replaced with a U. 
     Construct 13(5) implements a 14-5-14 design. 
     In case of “106-13(4)”, the first number (106) again indicates that the construct is derived from the guide sequence of SEQ ID NO: 106. The number 13 refers to a shortened duplex of 13 base pairs, and (4) refers to a loop region of 4 nucleotides. In other words, 106-13(4) is a molecules following a 13-4-13 design, with a guide sequence of 19 nucleotides, the 5′-terminal 13 nucleotides of which are involved in base pairing within a duplex region, the adjacent 4 nucleotides form the loop, and the two 3′-terminal nucleotides (positions 18 and 19 within the guide sequence) fold back and base pair with positions 13 and 12 of the guide sequence, respectively. Such spill-over (nucleotides of the guide sequence extending beyond the loop) allow for a further shortening of the passenger region which in this case has a length of 11 nucleotides only. The two 3′-terminal nucleotides of the guide region, together with the adjacent 11 nucleotides of the passenger region form a stretch of 13 contiguous nucleotides which base pair with the 5′-terminal 13 nucleotides of the guide region. As compared to construct 13(5), 106-13(4) is 3 nucleotides shorter, as a consequence of the spill-over and the loop being 4 instead of 5 nucleotides long. 
     Generally speaking, as used herein, “as” after the notation indicates that a sequence is an antisense sequence, whereas “s” indicates that the sequence is a sense sequence. Accordingly, an antisense strand linked to a sense strand is denoted “as+s”. 
     Tables 1a and 1b below show nucleobase sequences of antisense and sense strands of 250 oligomeric compounds in accordance with the Examples. The numbering in Table la coincides with the number of the corresponding entry in the sequence listing. For Table 1b the following applies: entry number in the sequence listing=entry number in the Table+250, except for entries “13(5) as”, referring to SEQ ID NO. 751 and “106-13(4) as”, referring to SEQ ID NO. 752 (Table la); and except for entries “13(5) s”, referring to SEQ ID NO. 753, and “106-13(4) s”, referring to SEQ ID NO. 754. 
     
       
         
           
               
             
               
                 TABLE la 
               
             
            
               
                   
               
               
                 Nucleobase sequences of the antisense strands 
               
               
                 of 252 constructs 
               
            
           
           
               
               
            
               
                 Experimental 
                   
               
               
                 Label 
                 19 mer Antisense 
               
               
                   
               
               
                 CFB01 
                 UAGAAAACCCAAAUCCUCA 
               
               
                   
               
               
                 CFB02 
                 GCUGUCUGAUCCAUCUAGC 
               
               
                   
               
               
                 CFB03 
                 AACCAUGCCACAGAGACUC 
               
               
                   
               
               
                 CFB04 
                 GAUCCAUCUAGCACCAGGU 
               
               
                   
               
               
                 CFB05 
                 AAAACCCAAAUCCUCAUCU 
               
               
                   
               
               
                 CFB06 
                 UCCAUCUAGCACCAGGUAG 
               
               
                   
               
               
                 CFB07 
                 GAAAACCCAAAUCCUCAUC 
               
               
                   
               
               
                 CFB08 
                 UGUCUGAUCCAUCUAGCAC 
               
               
                   
               
               
                 CFB09 
                 AACCCAAAUCCUCAUCUUG 
               
               
                   
               
               
                 CFB10 
                 AUCCAUCUAGCACCAGGUA 
               
               
                   
               
               
                 CFB11 
                 AAACCCAAAUCCUCAUCUU 
               
               
                   
               
               
                 CFB12 
                 CCAUGCCACAGAGACUCAG 
               
               
                   
               
               
                 CFB13 
                 AUGCCACAGAGACUCAGAG 
               
               
                   
               
               
                 CFB14 
                 GAUGAUGACAUGGCGGGUG 
               
               
                   
               
               
                 CFB15 
                 UUCCAUAUCCUUGACUUUG 
               
               
                   
               
               
                 CFB16 
                 UACACCAACUUGAAUGAAA 
               
               
                   
               
               
                 CFB17 
                 UGCCACAGAGACUCAGAGA 
               
               
                   
               
               
                 CFB18 
                 ACCAUGCCACAGAGACUCA 
               
               
                   
               
               
                 CFB19 
                 CCAUCUAGCACCAGGUAGA 
               
               
                   
               
               
                 CFB20 
                 UUUCCAUAUCCUUGACUUU 
               
               
                   
               
               
                 CFB21 
                 UGAUCCAUCUAGCACCAGG 
               
               
                   
               
               
                 CFB22 
                 GCCACAGAGACUCAGAGAC 
               
               
                   
               
               
                 CFB23 
                 CUGAUCCAUCUAGCACCAG 
               
               
                   
               
               
                 CFB24 
                 GACCUCCUUCCGAGUCAGC 
               
               
                   
               
               
                 CFB25 
                 GUCUGAUCCAUCUAGCACC 
               
               
                   
               
               
                 CFB26 
                 GUCUUGGCAGGAAGGCUCC 
               
               
                   
               
               
                 CFB27 
                 AUCUAGCACCAGGUAGAUG 
               
               
                   
               
               
                 CFB28 
                 AAAGUACUCAGACACCACA 
               
               
                   
               
               
                 CFB29 
                 CUGUCUGAUCCAUCUAGCA 
               
               
                   
               
               
                 CFB30 
                 CAUCUAGCACCAGGUAGAU 
               
               
                   
               
               
                 CFB31 
                 CCAAAUCCUCAUCUUGGAG 
               
               
                   
               
               
                 CFB32 
                 CAUAGUCAUAAAAUUCAGG 
               
               
                   
               
               
                 CFB33 
                 GAGGAUGAUGACAUGGCGG 
               
               
                   
               
               
                 CFB34 
                 ACAAUCUGUGUUCUGGCAC 
               
               
                   
               
               
                 CFB35 
                 UUGAGCUUGAUCAGGGCAA 
               
               
                   
               
               
                 CFB36 
                 CAGUGGAAAGAGAUCUCAU 
               
               
                   
               
               
                 CFB37 
                 UAGAUGUUCAUGGAGCCUG 
               
               
                   
               
               
                 CFB38 
                 GGCAAGUGGUAGUUGGAGG 
               
               
                   
               
               
                 CFB39 
                 UCACACCAUAACUUGCCAC 
               
               
                   
               
               
                 CFB40 
                 GAAAGAGAUCUCAUCACUC 
               
               
                   
               
               
                 CFB41 
                 UUCAACUUGUGGUCUUCAU 
               
               
                   
               
               
                 CFB42 
                 GAAACGACUUCUCUUGUGA 
               
               
                   
               
               
                 CFB43 
                 GGUAUGUGGCAUAUGUCAC 
               
               
                   
               
               
                 CFB44 
                 UGUCUUUCUUGGAAGCCAA 
               
               
                   
               
               
                 CFB45 
                 ACAUCCAGAUAAUCCUCCC 
               
               
                   
               
               
                 CFB46 
                 CUUGACUUUGUCAUAGCCU 
               
               
                   
               
               
                 CFB47 
                 GAAACUCCAGACCUAGACC 
               
               
                   
               
               
                 CFB48 
                 CAUAACUUGCCACCUUCUC 
               
               
                   
               
               
                 CFB49 
                 UCAUAGUCAUAAAAUUCAG 
               
               
                   
               
               
                 CFB50 
                 UUGGCUCCUGUGAAGUUGC 
               
               
                   
               
               
                 CFB51 
                 CAAAGUACUCAGACACCAC 
               
               
                   
               
               
                 CFB52 
                 UGCUCAUUGUCUUUCUUGG 
               
               
                   
               
               
                 CFB53 
                 AUAAAAUUCAGGAAUUCCU 
               
               
                   
               
               
                 CFB54 
                 UGAGAUCUUGGCCUGCCAU 
               
               
                   
               
               
                 CFB55 
                 UGAGCAUCUCUCUCACAGC 
               
               
                   
               
               
                 CFB56 
                 UAACCGUCAUAGCAGUGGA 
               
               
                   
               
               
                 CFB57 
                 CAGAGCUUUGAUAUCCUGU 
               
               
                   
               
               
                 CFB58 
                 AACAAUGUGCUGCUGUCAG 
               
               
                   
               
               
                 CFB59 
                 GGGUACGGGUAGAAGCCAG 
               
               
                   
               
               
                 CFB60 
                 CCAGACCUAGACCUGGUCA 
               
               
                   
               
               
                 CFB61 
                 CUUCUCUUGUGAACUAUCA 
               
               
                   
               
               
                 CFB62 
                 AUUCAGGAAUUCCUGCUUC 
               
               
                   
               
               
                 CFB63 
                 UCCAGGUUUUCCAUAUCCU 
               
               
                   
               
               
                 CFB64 
                 CCAACUUGAAUGAAACGAC 
               
               
                   
               
               
                 CFB65 
                 UGUGCUGCUGUCAGCACAA 
               
               
                   
               
               
                 CFB66 
                 AGACCUCCUUCCGAGUCAG 
               
               
                   
               
               
                 CFB67 
                 UCAAUUAAGUUGACUAGAC 
               
               
                   
               
               
                 CFB68 
                 CUGACACGUUCGCCGCUGG 
               
               
                   
               
               
                 CFB69 
                 UCAUUGUCUUUCUUGGAAG 
               
               
                   
               
               
                 CFB70 
                 ACCAACUUGAAUGAAACGA 
               
               
                   
               
               
                 CFB71 
                 GCACAAAGUACUCAGACAC 
               
               
                   
               
               
                 CFB72 
                 CUGCAGUGGUAGGUGACGC 
               
               
                   
               
               
                 CFB73 
                 GUCAUGAGGAUGAUGACAU 
               
               
                   
               
               
                 CFB74 
                 CUUCAACUUGUGGUCUUCA 
               
               
                   
               
               
                 CFB75 
                 GGUAGUUGGAGGAAGCCUC 
               
               
                   
               
               
                 CFB76 
                 UCAUGCUGUACACUGCCUG 
               
               
                   
               
               
                 CFB77 
                 UUGUCUUUCUUGGAAGCCA 
               
               
                   
               
               
                 CFB78 
                 UCGACUCCUUCUAUGGUCU 
               
               
                   
               
               
                 CFB79 
                 AGACAUCCAGAUAAUCCUC 
               
               
                   
               
               
                 CFB80 
                 CUGAGAUCUUGGCCUGCCA 
               
               
                   
               
               
                 CFB81 
                 GACGCUGUCUUCAAGGCGG 
               
               
                   
               
               
                 CFB82 
                 AAGACAGGAAAGCUUCGGC 
               
               
                   
               
               
                 CFB83 
                 UUUGAACACAUGUUGCUCA 
               
               
                   
               
               
                 CFB84 
                 CAUAAAAUUCAGGAAUUCC 
               
               
                   
               
               
                 CFB85 
                 ACCCAAAUCCUCAUCUUGG 
               
               
                   
               
               
                 CFB86 
                 AAAGAGAUCUCAUCACUCA 
               
               
                   
               
               
                 CFB87 
                 CAAAGCAUUGAUGUUCACU 
               
               
                   
               
               
                 CFB88 
                 CAGGAAUUCCUGCUUCUUU 
               
               
                   
               
               
                 CFB89 
                 CAUGAAGGAGUCUUGGCAG 
               
               
                   
               
               
                 CFB90 
                 AAAGCUUCGGCCACCUCUU 
               
               
                   
               
               
                 CFB91 
                 UUGACUUUGUCAUAGCCUG 
               
               
                   
               
               
                 CFB92 
                 GUCCAAGCUGAAACUCCAG 
               
               
                   
               
               
                 CFB93 
                 CCCAAAUCCUCAUCUUGGA 
               
               
                   
               
               
                 CFB94 
                 GCAGCUGUUUUAAUUCAAU 
               
               
                   
               
               
                 CFB95 
                 AAACGACUUCUCUUGUGAA 
               
               
                   
               
               
                 CFB96 
                 CCCGGAACAUCCAAGCGGG 
               
               
                   
               
               
                 CFB97 
                 CCAAACACAUAGACAUCCA 
               
               
                   
               
               
                 CFB98 
                 CUUCACACCAUAACUUGCC 
               
               
                   
               
               
                 CFB99 
                 UUCUCUUGUGAACUAUCAA 
               
               
                   
               
               
                 CFB100 
                 AAUUCAGGAAUUCCUGCUU 
               
               
                   
               
               
                 CFB101 
                 AGACACUUUGACCCAAAUU 
               
               
                   
               
               
                 CFB102 
                 ACACAAACAGAGCUUUGAU 
               
               
                   
               
               
                 CFB103 
                 ACAAACAGAGCUUUGAUAU 
               
               
                   
               
               
                 CFB104 
                 CUUGGAGUUUCUCCUUCAG 
               
               
                   
               
               
                 CFB105 
                 UUCACACCAUAACUUGCCA 
               
               
                   
               
               
                 CFB106 
                 UUGAAUGAAACGACUUCUC 
               
               
                   
               
               
                 CFB107 
                 CCAGGUUUUCCAUAUCCUU 
               
               
                   
               
               
                 CFB108 
                 AGCAUCUCUCUCACAGCUG 
               
               
                   
               
               
                 CFB109 
                 GACAUCCAGAUAAUCCUCC 
               
               
                   
               
               
                 CFB110 
                 UCGAGUUGUUCCCUCGGUG 
               
               
                   
               
               
                 CFB111 
                 AACACAUGUUGCUCAUUGU 
               
               
                   
               
               
                 CFB112 
                 UUCUCAAUUAAGUUGACUA 
               
               
                   
               
               
                 CFB113 
                 GGAAGCCAAAGCAUUGAUG 
               
               
                   
               
               
                 CFB114 
                 AGCAGUGGAAAGAGAUCUC 
               
               
                   
               
               
                 CFB115 
                 UACACUGCCUGGAGGGCCU 
               
               
                   
               
               
                 CFB116 
                 CUAGACCUGGUCACAUUCC 
               
               
                   
               
               
                 CFB117 
                 UCAGACACAAACAGAGCUU 
               
               
                   
               
               
                 CFB118 
                 GGAGUUUCUCCUUCAGCCA 
               
               
                   
               
               
                 CFB119 
                 AAUGUGCUGCUGUCAGCAC 
               
               
                   
               
               
                 CFB120 
                 ACAGAGCUUUGAUAUCCUG 
               
               
                   
               
               
                 CFB121 
                 UGAUAUCCUGUGCAGGGAG 
               
               
                   
               
               
                 CFB122 
                 CAGGGCAACGUCAUAGUCA 
               
               
                   
               
               
                 CFB123 
                 CAGACCUAGACCUGGUCAC 
               
               
                   
               
               
                 CFB124 
                 AAGUACUCAGACACCACAG 
               
               
                   
               
               
                 CFB125 
                 GAAGGCUCCGUCCCGCUCC 
               
               
                   
               
               
                 CFB126 
                 AGGGCAACGUCAUAGUCAU 
               
               
                   
               
               
                 CFB127 
                 GCUGUUUUAAUUCAAUCCC 
               
               
                   
               
               
                 CFB128 
                 AAGAGAUCUCAUCACUCAC 
               
               
                   
               
               
                 CFB129 
                 UGGUCUUCAUAAUUGAUUU 
               
               
                   
               
               
                 CFB130 
                 CCAUAUCUUGGCUUCACAC 
               
               
                   
               
               
                 CFB131 
                 ACACCAACUUGAAUGAAAC 
               
               
                   
               
               
                 CFB132 
                 CAGCUGUUUUAAUUCAAUC 
               
               
                   
               
               
                 CFB133 
                 AUAACUUGCCACCUUCUCA 
               
               
                   
               
               
                 CFB134 
                 GUGAGCAGGUACCUGCUUU 
               
               
                   
               
               
                 CFB135 
                 CUUGAUGUAGACCUCCUUC 
               
               
                   
               
               
                 CFB136 
                 UGGCAAGUGGUAGUUGGAG 
               
               
                   
               
               
                 CFB137 
                 AGGAAGCCUCAAAGCUCGA 
               
               
                   
               
               
                 CFB138 
                 CAAUGACAGUAAUUGGGUC 
               
               
                   
               
               
                 CFB139 
                 CUUUGAACACAUGUUGCUC 
               
               
                   
               
               
                 CFB140 
                 CAAAUCCUCAUCUUGGAGU 
               
               
                   
               
               
                 CFB141 
                 UGGAGUUUCUCCUUCAGCC 
               
               
                   
               
               
                 CFB142 
                 CCAUAACUUGCCACCUUCU 
               
               
                   
               
               
                 CFB143 
                 AGCUGUUUUAAUUCAAUCC 
               
               
                   
               
               
                 CFB144 
                 AAAGCUCGAGUUGUUCCCU 
               
               
                   
               
               
                 CFB145 
                 GGGCAACGUCAUAGUCAUA 
               
               
                   
               
               
                 CFB146 
                 CUUCCAGGUUUUCCAUAUC 
               
               
                   
               
               
                 CFB147 
                 UUCCAGGUUUUCCAUAUCC 
               
               
                   
               
               
                 CFB148 
                 CCCAUGUUGUGCAAUCCAU 
               
               
                   
               
               
                 CFB149 
                 CCAUAUCCUUGACUUUGAA 
               
               
                   
               
               
                 CFB150 
                 UUGACUUUGAACACAUGUU 
               
               
                   
               
               
                 CFB151 
                 CCUCAUCUUGGAGUUUCUC 
               
               
                   
               
               
                 CFB152 
                 ACAUGUUGCUCAUUGUCUU 
               
               
                   
               
               
                 CFB153 
                 CACCAACUUGAAUGAAACG 
               
               
                   
               
               
                 CFB154 
                 CACAGAUCGCUGUCUGCCC 
               
               
                   
               
               
                 CFB155 
                 CUCACAGCUGCCUUUCUUA 
               
               
                   
               
               
                 CFB156 
                 GGGCCGCCAGAAUCACCUC 
               
               
                   
               
               
                 CFB157 
                 UCCAAGCUGAAACUCCAGA 
               
               
                   
               
               
                 CFB158 
                 CUUGAUCAGGGCAACGUCA 
               
               
                   
               
               
                 CFB159 
                 UGUUCCCAAACCAUGCCAC 
               
               
                   
               
               
                 CFB160 
                 UACCUGCUUUUGCCGCUUC 
               
               
                   
               
               
                 CFB161 
                 GUUGCUCAUUGUCUUUCUU 
               
               
                   
               
               
                 CFB162 
                 ACACGUUCGCCGCUGGGAG 
               
               
                   
               
               
                 CFB163 
                 CCAUUCUUGAUGUAGACCU 
               
               
                   
               
               
                 CFB164 
                 CUUGAGCUUGAUCAGGGCA 
               
               
                   
               
               
                 CFB165 
                 CAUUCUUGAUGUAGACCUC 
               
               
                   
               
               
                 CFB166 
                 AUGAAGGAGUCUUGGCAGG 
               
               
                   
               
               
                 CFB167 
                 CUUGGCUUCACACCAUAAC 
               
               
                   
               
               
                 CFB168 
                 UAUCUUGGCUUCACACCAU 
               
               
                   
               
               
                 CFB169 
                 UCUCACAGCUGCCUUUCUU 
               
               
                   
               
               
                 CFB170 
                 CCCAAUGCUGUCUGAUCCA 
               
               
                   
               
               
                 CFB171 
                 GGAGUGGUGGUCACACCUC 
               
               
                   
               
               
                 CFB172 
                 CAUAGGGACUCACUCCUCC 
               
               
                   
               
               
                 CFB173 
                 CCUGACUUCAACUUGUGGU 
               
               
                   
               
               
                 CFB174 
                 CUUCUCAAUUAAGUUGACU 
               
               
                   
               
               
                 CFB175 
                 GAGUUUCUCCUUCAGCCAG 
               
               
                   
               
               
                 CFB176 
                 GAGCUUUGAUAUCCUGUGC 
               
               
                   
               
               
                 CFB177 
                 AUGUCCUUGACUUUGUCAU 
               
               
                   
               
               
                 CFB178 
                 GCAGGUACGUGUCUGCACA 
               
               
                   
               
               
                 CFB179 
                 GAAACAAUGUGCUGCUGUC 
               
               
                   
               
               
                 CFB180 
                 GAUAUCCUGUGCAGGGAGC 
               
               
                   
               
               
                 CFB181 
                 AGACUCAGAGACUGGCUUU 
               
               
                   
               
               
                 CFB182 
                 UCAAUGACAGUAAUUGGGU 
               
               
                   
               
               
                 CFB183 
                 AGAGCCACCUUCCUGACAC 
               
               
                   
               
               
                 CFB184 
                 CCUUGACUUUGAACACAUG 
               
               
                   
               
               
                 CFB185 
                 AAUGAAACGACUUCUCUUG 
               
               
                   
               
               
                 CFB186 
                 GGAAGACAGGAAAGCUUCG 
               
               
                   
               
               
                 CFB187 
                 AGCUUUGAUAUCCUGUGCA 
               
               
                   
               
               
                 CFB188 
                 UUCUUGAGCUUGAUCAGGG 
               
               
                   
               
               
                 CFB189 
                 UGGAUUGCUCUGCACUCUG 
               
               
                   
               
               
                 CFB190 
                 GCAUAUUGAGCAUCUCUCU 
               
               
                   
               
               
                 CFB191 
                 UAUCCUUGACUUUGAACAC 
               
               
                   
               
               
                 CFB192 
                 UGCAGACAUCCACUACUCC 
               
               
                   
               
               
                 CFB193 
                 UAGACCUCCUUCCGAGUCA 
               
               
                   
               
               
                 CFB194 
                 CACCUUCUCAAUUAAGUUG 
               
               
                   
               
               
                 CFB195 
                 GAGAAGUCGGAAGGAGCCG 
               
               
                   
               
               
                 CFB196 
                 CUGCACAGGGUACGGGUAG 
               
               
                   
               
               
                 CFB197 
                 AAUGACAGUAAUUGGGUCC 
               
               
                   
               
               
                 CFB198 
                 UGUUAGUCCCUGACUUCAA 
               
               
                   
               
               
                 CFB199 
                 CAUAUCCUUGACUUUGAAC 
               
               
                   
               
               
                 CFB200 
                 GGUACGUGUCUGCACAGGG 
               
               
                   
               
               
                 CFB201 
                 UGUCAGCACAAAGUACUCA 
               
               
                   
               
               
                 CFB202 
                 GUGGUCUUCAUAAUUGAUU 
               
               
                   
               
               
                 CFB203 
                 ACAGAGACUCAGAGACUGG 
               
               
                   
               
               
                 CFB204 
                 AUAGACAUCCAGAUAAUCC 
               
               
                   
               
               
                 CFB205 
                 CCUCCUUCCGAGUCAGCUU 
               
               
                   
               
               
                 CFB206 
                 UCAUGGAGCCUGAAGGGUC 
               
               
                   
               
               
                 CFB207 
                 GUGGCAUAUGUCACUAGAC 
               
               
                   
               
               
                 CFB208 
                 AAAGCAUUGAUGUUCACUU 
               
               
                   
               
               
                 CFB209 
                 ACUCACUCCUCCAGUACAA 
               
               
                   
               
               
                 CFB210 
                 AGAUGUCCUUGACUUUGUC 
               
               
                   
               
               
                 CFB211 
                 CUGUUUUAAUUCAAUCCCA 
               
               
                   
               
               
                 CFB212 
                 GUAGAUGUUCAUGGAGCCU 
               
               
                   
               
               
                 CFB213 
                 CAUAGCAGUGGAAAGAGAU 
               
               
                   
               
               
                 CFB214 
                 CCAUUCACUUGGCAGGUGC 
               
               
                   
               
               
                 CFB215 
                 CAUUGAUGUUCACUUGGUU 
               
               
                   
               
               
                 CFB216 
                 UCAGCCAGGGCAGCACUUG 
               
               
                   
               
               
                 CFB217 
                 GCUCAGUGUCCAAGCUGAA 
               
               
                   
               
               
                 CFB218 
                 UCAGAGACUGGCUUUCAUC 
               
               
                   
               
               
                 CFB219 
                 CAUCCAGAUAAUCCUCCCU 
               
               
                   
               
               
                 CFB220 
                 CCUUCUCAAUUAAGUUGAC 
               
               
                   
               
               
                 CFB221 
                 UCCAGACCUAGACCUGGUC 
               
               
                   
               
               
                 CFB222 
                 GCAACGUCAUAGUCAUAAA 
               
               
                   
               
               
                 CFB223 
                 CUUGAAUGAAACGACUUCU 
               
               
                   
               
               
                 CFB224 
                 UCCUCCUCAGACACAAACA 
               
               
                   
               
               
                 CFB225 
                 GAAGCCAAAGCAUUGAUGU 
               
               
                   
               
               
                 CFB226 
                 AUGAAACGACUUCUCUUGU 
               
               
                   
               
               
                 CFB227 
                 CAACUUGUGGUCUUCAUAA 
               
               
                   
               
               
                 CFB228 
                 ACCAGGUAGAUGUUCAUGG 
               
               
                   
               
               
                 CFB229 
                 UCUGUGUUCUGGCACCUGC 
               
               
                   
               
               
                 CFB230 
                 UAACUUGCCACCUUCUCAA 
               
               
                   
               
               
                 CFB231 
                 UGCCAUGGUUGCUUGUGGU 
               
               
                   
               
               
                 CFB232 
                 AGACAAAUGGGCCUGAUAG 
               
               
                   
               
               
                 CFB233 
                 UAAGUUGACUAGACACUUU 
               
               
                   
               
               
                 CFB234 
                 ACAUGGCGGGUGCGGUUCC 
               
               
                   
               
               
                 CFB235 
                 CCCGGAUCUCAUCAAUGAC 
               
               
                   
               
               
                 CFB236 
                 GGAGGAAGCCUCAAAGCUC 
               
               
                   
               
               
                 CFB237 
                 GACUUUGAACACAUGUUGC 
               
               
                   
               
               
                 CFB238 
                 UCUCCUCCUCAGACACAAA 
               
               
                   
               
               
                 CFB239 
                 CAGGAAGGCUCCGUCCCGC 
               
               
                   
               
               
                 CFB240 
                 CCGCCAGAAUCACCUCUGC 
               
               
                   
               
               
                 CFB241 
                 UGGAAAGAGAUCUCAUCAC 
               
               
                   
               
               
                 CFB242 
                 CAAGUCCCGGAUCUCAUCA 
               
               
                   
               
               
                 CFB243 
                 UGAGCUUGAUCAGGGCAAC 
               
               
                   
               
               
                 CFB244 
                 UGUUGCUCAUUGUCUUUCU 
               
               
                   
               
               
                 CFB245 
                 UUGCUUGUGGUAAUCGGUA 
               
               
                   
               
               
                 CFB246 
                 CUCAUCACUCACAUUGUAG 
               
               
                   
               
               
                 CFB247 
                 UCAGUGUCCAAGCUGAAAC 
               
               
                   
               
               
                 CFB248 
                 CCCAUUCUUGAUGUAGACC 
               
               
                   
               
               
                 CFB249 
                 AAACAAUGUGCUGCUGUCA 
               
               
                   
               
               
                 CFB250 
                 UGACUUCAACUUGUGGUCU 
               
               
                   
               
               
                 13(5) as 
                 UUGCCACAGAGACUCAGAG 
               
               
                   
               
               
                 106-13(4) as 
                 UUGAAUGAAACGACUUCUC 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 1b 
               
             
            
               
                   
               
               
                 Nucleobase sequences of the sense strands of 
               
               
                 252 constructs 
               
            
           
           
               
               
            
               
                 Experimental 
                   
               
               
                 Label 
                 15 mer, 14 mer or 11 mer Sense 
               
               
                   
               
               
                 CFB01 
                 GAUUUGGGUUUUCUA 
               
               
                   
               
               
                 CFB02 
                 GAUGGAUCAGACAGC 
               
               
                   
               
               
                 CFB03 
                 CUCUGUGGCAUGGUU 
               
               
                   
               
               
                 CFB04 
                 GGUGCUAGAUGGAUC 
               
               
                   
               
               
                 CFB05 
                 GAGGAUUUGGGUUUU 
               
               
                   
               
               
                 CFB06 
                 CUGGUGCUAGAUGGA 
               
               
                   
               
               
                 CFB07 
                 AGGAUUUGGGUUUUC 
               
               
                   
               
               
                 CFB08 
                 UAGAUGGAUCAGACA 
               
               
                   
               
               
                 CFB09 
                 AUGAGGAUUUGGGUU 
               
               
                   
               
               
                 CFB10 
                 UGGUGCUAGAUGGAU 
               
               
                   
               
               
                 CFB11 
                 UGAGGAUUUGGGUUU 
               
               
                   
               
               
                 CFB12 
                 GUCUCUGUGGCAUGG 
               
               
                   
               
               
                 CFB13 
                 GAGUCUCUGUGGCAU 
               
               
                   
               
               
                 CFB14 
                 CGCCAUGUCAUCAUC 
               
               
                   
               
               
                 CFB15 
                 GUCAAGGAUAUGGAA 
               
               
                   
               
               
                 CFB16 
                 AUUCAAGUUGGUGUA 
               
               
                   
               
               
                 CFB17 
                 UGAGUCUCUGUGGCA 
               
               
                   
               
               
                 CFB18 
                 UCUCUGUGGCAUGGU 
               
               
                   
               
               
                 CFB19 
                 CCUGGUGCUAGAUGG 
               
               
                   
               
               
                 CFB20 
                 UCAAGGAUAUGGAAA 
               
               
                   
               
               
                 CFB21 
                 GUGCUAGAUGGAUCA 
               
               
                   
               
               
                 CFB22 
                 CUGAGUCUCUGUGGC 
               
               
                   
               
               
                 CFB23 
                 UGCUAGAUGGAUCAG 
               
               
                   
               
               
                 CFB24 
                 ACUCGGAAGGAGGUC 
               
               
                   
               
               
                 CFB25 
                 CUAGAUGGAUCAGAC 
               
               
                   
               
               
                 CFB26 
                 CCUUCCUGCCAAGAC 
               
               
                   
               
               
                 CFB27 
                 UACCUGGUGCUAGAU 
               
               
                   
               
               
                 CFB28 
                 GUGUCUGAGUACUUU 
               
               
                   
               
               
                 CFB29 
                 AGAUGGAUCAGACAG 
               
               
                   
               
               
                 CFB30 
                 ACCUGGUGCUAGAUG 
               
               
                   
               
               
                 CFB31 
                 AAGAUGAGGAUUUGG 
               
               
                   
               
               
                 CFB32 
                 AAUUUUAUGACUAUG 
               
               
                   
               
               
                 CFB33 
                 CAUGUCAUCAUCCUC 
               
               
                   
               
               
                 CFB34 
                 CAGAACACAGAUUGU 
               
               
                   
               
               
                 CFB35 
                 CCUGAUCAAGCUCAA 
               
               
                   
               
               
                 CFB36 
                 GAUCUCUUUCCACUG 
               
               
                   
               
               
                 CFB37 
                 CUCCAUGAACAUCUA 
               
               
                   
               
               
                 CFB38 
                 CAACUACCACUUGCC 
               
               
                   
               
               
                 CFB39 
                 CAAGUUAUGGUGUGA 
               
               
                   
               
               
                 CFB40 
                 GAUGAGAUCUCUUUC 
               
               
                   
               
               
                 CFB41 
                 AGACCACAAGUUGAA 
               
               
                   
               
               
                 CFB42 
                 AAGAGAAGUCGUUUC 
               
               
                   
               
               
                 CFB43 
                 CAUAUGCCACAUACC 
               
               
                   
               
               
                 CFB44 
                 CUUCCAAGAAAGACA 
               
               
                   
               
               
                 CFB45 
                 GGAUUAUCUGGAUGU 
               
               
                   
               
               
                 CFB46 
                 UAUGACAAAGUCAAG 
               
               
                   
               
               
                 CFB47 
                 UAGGUCUGGAGUUUC 
               
               
                   
               
               
                 CFB48 
                 AGGUGGCAAGUUAUG 
               
               
                   
               
               
                 CFB49 
                 AUUUUAUGACUAUGA 
               
               
                   
               
               
                 CFB50 
                 CUUCACAGGAGCCAA 
               
               
                   
               
               
                 CFB51 
                 UGUCUGAGUACUUUG 
               
               
                   
               
               
                 CFB52 
                 GAAAGACAAUGAGCA 
               
               
                   
               
               
                 CFB53 
                 AUUCCUGAAUUUUAU 
               
               
                   
               
               
                 CFB54 
                 CAGGCCAAGAUCUCA 
               
               
                   
               
               
                 CFB55 
                 UGAGAGAGAUGCUCA 
               
               
                   
               
               
                 CFB56 
                 CUGCUAUGACGGUUA 
               
               
                   
               
               
                 CFB57 
                 GAUAUCAAAGCUCUG 
               
               
                   
               
               
                 CFB58 
                 CAGCAGCACAUUGUU 
               
               
                   
               
               
                 CFB59 
                 CUUCUACCCGUACCC 
               
               
                   
               
               
                 CFB60 
                 CAGGUCUAGGUCUGG 
               
               
                   
               
               
                 CFB61 
                 AGUUCACAAGAGAAG 
               
               
                   
               
               
                 CFB62 
                 CAGGAAUUCCUGAAU 
               
               
                   
               
               
                 CFB63 
                 UAUGGAAAACCUGGA 
               
               
                   
               
               
                 CFB64 
                 UUUCAUUCAAGUUGG 
               
               
                   
               
               
                 CFB65 
                 GCUGACAGCAGCACA 
               
               
                   
               
               
                 CFB66 
                 CUCGGAAGGAGGUCU 
               
               
                   
               
               
                 CFB67 
                 AGUCAACUUAAUUGA 
               
               
                   
               
               
                 CFB68 
                 CGGCGAACGUGUCAG 
               
               
                   
               
               
                 CFB69 
                 CAAGAAAGACAAUGA 
               
               
                   
               
               
                 CFB70 
                 UUCAUUCAAGUUGGU 
               
               
                   
               
               
                 CFB71 
                 CUGAGUACUUUGUGC 
               
               
                   
               
               
                 CFB72 
                 CACCUACCACUGCAG 
               
               
                   
               
               
                 CFB73 
                 CAUCAUCCUCAUGAC 
               
               
                   
               
               
                 CFB74 
                 GACCACAAGUUGAAG 
               
               
                   
               
               
                 CFB75 
                 CUUCCUCCAACUACC 
               
               
                   
               
               
                 CFB76 
                 CAGUGUACAGCAUGA 
               
               
                   
               
               
                 CFB77 
                 UUCCAAGAAAGACAA 
               
               
                   
               
               
                 CFB78 
                 CAUAGAAGGAGUCGA 
               
               
                   
               
               
                 CFB79 
                 AUUAUCUGGAUGUCU 
               
               
                   
               
               
                 CFB80 
                 AGGCCAAGAUCUCAG 
               
               
                   
               
               
                 CFB81 
                 CUUGAAGACAGCGUC 
               
               
                   
               
               
                 CFB82 
                 AAGCUUUCCUGUCUU 
               
               
                   
               
               
                 CFB83 
                 CAACAUGUGUUCAAA 
               
               
                   
               
               
                 CFB84 
                 UUCCUGAAUUUUAUG 
               
               
                   
               
               
                 CFB85 
                 GAUGAGGAUUUGGGU 
               
               
                   
               
               
                 CFB86 
                 UGAUGAGAUCUCUUU 
               
               
                   
               
               
                 CFB87 
                 AACAUCAAUGCUUUG 
               
               
                   
               
               
                 CFB88 
                 AAGCAGGAAUUCCUG 
               
               
                   
               
               
                 CFB89 
                 CAAGACUCCUUCAUG 
               
               
                   
               
               
                 CFB90 
                 GGUGGCCGAAGCUUU 
               
               
                   
               
               
                 CFB91 
                 CUAUGACAAAGUCAA 
               
               
                   
               
               
                 CFB92 
                 AGUUUCAGCUUGGAC 
               
               
                   
               
               
                 CFB93 
                 AGAUGAGGAUUUGGG 
               
               
                   
               
               
                 CFB94 
                 AAUUAAAACAGCUGC 
               
               
                   
               
               
                 CFB95 
                 CAAGAGAAGUCGUUU 
               
               
                   
               
               
                 CFB96 
                 CUUGGAUGUUCCGGG 
               
               
                   
               
               
                 CFB97 
                 UGUCUAUGUGUUUGG 
               
               
                   
               
               
                 CFB98 
                 AGUUAUGGUGUGAAG 
               
               
                   
               
               
                 CFB99 
                 UAGUUCACAAGAGAA 
               
               
                   
               
               
                 CFB100 
                 AGGAAUUCCUGAAUU 
               
               
                   
               
               
                 CFB101 
                 UGGGUCAAAGUGUCU 
               
               
                   
               
               
                 CFB102 
                 AAGCUCUGUUUGUGU 
               
               
                   
               
               
                 CFB103 
                 CAAAGCUCUGUUUGU 
               
               
                   
               
               
                 CFB104 
                 AGGAGAAACUCCAAG 
               
               
                   
               
               
                 CFB105 
                 AAGUUAUGGUGUGAA 
               
               
                   
               
               
                 CFB106 
                 AGUCGUUUCAUUCAA 
               
               
                   
               
               
                 CFB107 
                 AUAUGGAAAACCUGG 
               
               
                   
               
               
                 CFB108 
                 UGUGAGAGAGAUGCU 
               
               
                   
               
               
                 CFB109 
                 GAUUAUCUGGAUGUC 
               
               
                   
               
               
                 CFB110 
                 GAGGGAACAACUCGA 
               
               
                   
               
               
                 CFB111 
                 UGAGCAACAUGUGUU 
               
               
                   
               
               
                 CFB112 
                 CAACUUAAUUGAGAA 
               
               
                   
               
               
                 CFB113 
                 AAUGCUUUGGCUUCC 
               
               
                   
               
               
                 CFB114 
                 UCUCUUUCCACUGCU 
               
               
                   
               
               
                 CFB115 
                 CCUCCAGGCAGUGUA 
               
               
                   
               
               
                 CFB116 
                 UGUGACCAGGUCUAG 
               
               
                   
               
               
                 CFB117 
                 UCUGUUUGUGUCUGA 
               
               
                   
               
               
                 CFB118 
                 UGAAGGAGAAACUCC 
               
               
                   
               
               
                 CFB119 
                 UGACAGCAGCACAUU 
               
               
                   
               
               
                 CFB120 
                 AUAUCAAAGCUCUGU 
               
               
                   
               
               
                 CFB121 
                 CUGCACAGGAUAUCA 
               
               
                   
               
               
                 CFB122 
                 UAUGACGUUGCCCUG 
               
               
                   
               
               
                 CFB123 
                 CCAGGUCUAGGUCUG 
               
               
                   
               
               
                 CFB124 
                 GGUGUCUGAGUACUU 
               
               
                   
               
               
                 CFB125 
                 CGGGACGGAGCCUUC 
               
               
                   
               
               
                 CFB126 
                 CUAUGACGUUGCCCU 
               
               
                   
               
               
                 CFB127 
                 UUGAAUUAAAACAGC 
               
               
                   
               
               
                 CFB128 
                 GUGAUGAGAUCUCUU 
               
               
                   
               
               
                 CFB129 
                 CAAUUAUGAAGACCA 
               
               
                   
               
               
                 CFB130 
                 GAAGCCAAGAUAUGG 
               
               
                   
               
               
                 CFB131 
                 CAUUCAAGUUGGUGU 
               
               
                   
               
               
                 CFB132 
                 GAAUUAAAACAGCUG 
               
               
                   
               
               
                 CFB133 
                 AAGGUGGCAAGUUAU 
               
               
                   
               
               
                 CFB134 
                 CAGGUACCUGCUCAC 
               
               
                   
               
               
                 CFB135 
                 GAGGUCUACAUCAAG 
               
               
                   
               
               
                 CFB136 
                 AACUACCACUUGCCA 
               
               
                   
               
               
                 CFB137 
                 GCUUUGAGGCUUCCU 
               
               
                   
               
               
                 CFB138 
                 CAAUUACUGUCAUUG 
               
               
                   
               
               
                 CFB139 
                 AACAUGUGUUCAAAG 
               
               
                   
               
               
                 CFB140 
                 CAAGAUGAGGAUUUG 
               
               
                   
               
               
                 CFB141 
                 GAAGGAGAAACUCCA 
               
               
                   
               
               
                 CFB142 
                 GGUGGCAAGUUAUGG 
               
               
                   
               
               
                 CFB143 
                 UGAAUUAAAACAGCU 
               
               
                   
               
               
                 CFB144 
                 AACAACUCGAGCUUU 
               
               
                   
               
               
                 CFB145 
                 ACUAUGACGUUGCCC 
               
               
                   
               
               
                 CFB146 
                 UGGAAAACCUGGAAG 
               
               
                   
               
               
                 CFB147 
                 AUGGAAAACCUGGAA 
               
               
                   
               
               
                 CFB148 
                 AUUGCACAACAUGGG 
               
               
                   
               
               
                 CFB149 
                 AAGUCAAGGAUAUGG 
               
               
                   
               
               
                 CFB150 
                 UGUGUUCAAAGUCAA 
               
               
                   
               
               
                 CFB151 
                 AACUCCAAGAUGAGG 
               
               
                   
               
               
                 CFB152 
                 CAAUGAGCAACAUGU 
               
               
                   
               
               
                 CFB153 
                 UCAUUCAAGUUGGUG 
               
               
                   
               
               
                 CFB154 
                 AGACAGCGAUCUGUG 
               
               
                   
               
               
                 CFB155 
                 AAAGGCAGCUGUGAG 
               
               
                   
               
               
                 CFB156 
                 UGAUUCUGGCGGCCC 
               
               
                   
               
               
                 CFB157 
                 GAGUUUCAGCUUGGA 
               
               
                   
               
               
                 CFB158 
                 GUUGCCCUGAUCAAG 
               
               
                   
               
               
                 CFB159 
                 CAUGGUUUGGGAACA 
               
               
                   
               
               
                 CFB160 
                 CGGCAAAAGCAGGUA 
               
               
                   
               
               
                 CFB161 
                 AAGACAAUGAGCAAC 
               
               
                   
               
               
                 CFB162 
                 CAGCGGCGAACGUGU 
               
               
                   
               
               
                 CFB163 
                 CUACAUCAAGAAUGG 
               
               
                   
               
               
                 CFB164 
                 CUGAUCAAGCUCAAG 
               
               
                   
               
               
                 CFB165 
                 UCUACAUCAAGAAUG 
               
               
                   
               
               
                 CFB166 
                 CCAAGACUCCUUCAU 
               
               
                   
               
               
                 CFB167 
                 UGGUGUGAAGCCAAG 
               
               
                   
               
               
                 CFB168 
                 UGUGAAGCCAAGAUA 
               
               
                   
               
               
                 CFB169 
                 AAGGCAGCUGUGAGA 
               
               
                   
               
               
                 CFB170 
                 UCAGACAGCAUUGGG 
               
               
                   
               
               
                 CFB171 
                 UGUGACCACCACUCC 
               
               
                   
               
               
                 CFB172 
                 GAGUGAGUCCCUAUG 
               
               
                   
               
               
                 CFB173 
                 CAAGUUGAAGUCAGG 
               
               
                   
               
               
                 CFB174 
                 AACUUAAUUGAGAAG 
               
               
                   
               
               
                 CFB175 
                 CUGAAGGAGAAACUC 
               
               
                   
               
               
                 CFB176 
                 AGGAUAUCAAAGCUC 
               
               
                   
               
               
                 CFB177 
                 CAAAGUCAAGGACAU 
               
               
                   
               
               
                 CFB178 
                 CAGACACGUACCUGC 
               
               
                   
               
               
                 CFB179 
                 GCAGCACAUUGUUUC 
               
               
                   
               
               
                 CFB180 
                 CCUGCACAGGAUAUC 
               
               
                   
               
               
                 CFB181 
                 CCAGUCUCUGAGUCU 
               
               
                   
               
               
                 CFB182 
                 AAUUACUGUCAUUGA 
               
               
                   
               
               
                 CFB183 
                 CAGGAAGGUGGCUCU 
               
               
                   
               
               
                 CFB184 
                 UGUUCAAAGUCAAGG 
               
               
                   
               
               
                 CFB185 
                 AGAAGUCGUUUCAUU 
               
               
                   
               
               
                 CFB186 
                 GCUUUCCUGUCUUCC 
               
               
                   
               
               
                 CFB187 
                 CAGGAUAUCAAAGCU 
               
               
                   
               
               
                 CFB188 
                 GAUCAAGCUCAAGAA 
               
               
                   
               
               
                 CFB189 
                 GUGCAGAGCAAUCCA 
               
               
                   
               
               
                 CFB190 
                 AGAUGCUCAAUAUGC 
               
               
                   
               
               
                 CFB191 
                 UCAAAGUCAAGGAUA 
               
               
                   
               
               
                 CFB192 
                 UAGUGGAUGUCUGCA 
               
               
                   
               
               
                 CFB193 
                 UCGGAAGGAGGUCUA 
               
               
                   
               
               
                 CFB194 
                 UUAAUUGAGAAGGUG 
               
               
                   
               
               
                 CFB195 
                 UCCUUCCGACUUCUC 
               
               
                   
               
               
                 CFB196 
                 CCGUACCCUGUGCAG 
               
               
                   
               
               
                 CFB197 
                 CCAAUUACUGUCAUU 
               
               
                   
               
               
                 CFB198 
                 AGUCAGGGACUAACA 
               
               
                   
               
               
                 CFB199 
                 AAAGUCAAGGAUAUG 
               
               
                   
               
               
                 CFB200 
                 GUGCAGACACGUACC 
               
               
                   
               
               
                 CFB201 
                 UACUUUGUGCUGACA 
               
               
                   
               
               
                 CFB202 
                 AAUUAUGAAGACCAC 
               
               
                   
               
               
                 CFB203 
                 UCUCUGAGUCUCUGU 
               
               
                   
               
               
                 CFB204 
                 UAUCUGGAUGUCUAU 
               
               
                   
               
               
                 CFB205 
                 UGACUCGGAAGGAGG 
               
               
                   
               
               
                 CFB206 
                 CUUCAGGCUCCAUGA 
               
               
                   
               
               
                 CFB207 
                 AGUGACAUAUGCCAC 
               
               
                   
               
               
                 CFB208 
                 GAACAUCAAUGCUUU 
               
               
                   
               
               
                 CFB209 
                 ACUGGAGGAGUGAGU 
               
               
                   
               
               
                 CFB210 
                 AAGUCAAGGACAUCU 
               
               
                   
               
               
                 CFB211 
                 AUUGAAUUAAAACAG 
               
               
                   
               
               
                 CFB212 
                 UCCAUGAACAUCUAC 
               
               
                   
               
               
                 CFB213 
                 CUUUCCACUGCUAUG 
               
               
                   
               
               
                 CFB214 
                 CUGCCAAGUGAAUGG 
               
               
                   
               
               
                 CFB215 
                 AAGUGAACAUCAAUG 
               
               
                   
               
               
                 CFB216 
                 UGCUGCCCUGGCUGA 
               
               
                   
               
               
                 CFB217 
                 GCUUGGACACUGAGC 
               
               
                   
               
               
                 CFB218 
                 AAAGCCAGUCUCUGA 
               
               
                   
               
               
                 CFB219 
                 AGGAUUAUCUGGAUG 
               
               
                   
               
               
                 CFB220 
                 ACUUAAUUGAGAAGG 
               
               
                   
               
               
                 CFB221 
                 AGGUCUAGGUCUGGA 
               
               
                   
               
               
                 CFB222 
                 UGACUAUGACGUUGC 
               
               
                   
               
               
                 CFB223 
                 GUCGUUUCAUUCAAG 
               
               
                   
               
               
                 CFB224 
                 UGUGUCUGAGGAGGA 
               
               
                   
               
               
                 CFB225 
                 CAAUGCUUUGGCUUC 
               
               
                   
               
               
                 CFB226 
                 GAGAAGUCGUUUCAU 
               
               
                   
               
               
                 CFB227 
                 GAAGACCACAAGUUG 
               
               
                   
               
               
                 CFB228 
                 GAACAUCUACCUGGU 
               
               
                   
               
               
                 CFB229 
                 GUGCCAGAACACAGA 
               
               
                   
               
               
                 CFB230 
                 GAAGGUGGCAAGUUA 
               
               
                   
               
               
                 CFB231 
                 CAAGCAACCAUGGCA 
               
               
                   
               
               
                 CFB232 
                 CAGGCCCAUUUGUCU 
               
               
                   
               
               
                 CFB233 
                 UGUCUAGUCAACUUA 
               
               
                   
               
               
                 CFB234 
                 CCGCACCCGCCAUGU 
               
               
                   
               
               
                 CFB235 
                 UUGAUGAGAUCCGGG 
               
               
                   
               
               
                 CFB236 
                 UUUGAGGCUUCCUCC 
               
               
                   
               
               
                 CFB237 
                 CAUGUGUUCAAAGUC 
               
               
                   
               
               
                 CFB238 
                 UGUCUGAGGAGGAGA 
               
               
                   
               
               
                 CFB239 
                 GACGGAGCCUUCCUG 
               
               
                   
               
               
                 CFB240 
                 AGGUGAUUCUGGCGG 
               
               
                   
               
               
                 CFB241 
                 UGAGAUCUCUUUCCA 
               
               
                   
               
               
                 CFB242 
                 GAGAUCCGGGACUUG 
               
               
                   
               
               
                 CFB243 
                 CCCUGAUCAAGCUCA 
               
               
                   
               
               
                 CFB244 
                 AGACAAUGAGCAACA 
               
               
                   
               
               
                 CFB245 
                 GAUUACCACAAGCAA 
               
               
                   
               
               
                 CFB246 
                 AAUGUGAGUGAUGAG 
               
               
                   
               
               
                 CFB247 
                 CAGCUUGGACACUGA 
               
               
                   
               
               
                 CFB248 
                 UACAUCAAGAAUGGG 
               
               
                   
               
               
                 CFB249 
                 AGCAGCACAUUGUUU 
               
               
                   
               
               
                 CFB250 
                 CACAAGUUGAAGUCA 
               
               
                   
               
               
                 13(5) s 
                 AGUCUCUGUGGCAA 
               
               
                   
               
               
                 106-13(4) s 
                 GUUUCAUUCAA 
               
               
                   
               
            
           
         
       
     
     Table 2 below shows the nucleobase sequences of 250 hairpin constructs selected in accordance with the Examples. The nucleobase sequences are a direct fusion of the antisense sequences of Table la with the corresponding sense sequences of Table lb. For Table 2 the following applies: entry number in the sequence listing =entry number in the Table+500, except for the construct denoted “13(5) as+s” which refers to SEQ ID NO. 755 and the construct denoted “106-13(4) as+s” which refers to SEQ ID NO. 756. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Nucleobase sequences of 252 constructs 
               
            
           
           
               
               
            
               
                 Experimental 
                 Sequence of 34 mer, 33 mer or 
               
               
                 Label 
                 30 mer Hairpin 
               
               
                   
               
               
                 CFB01 
                 UAGAAAACCCAAAUCCUCAGAUUUGGGUUUUCUA 
               
               
                   
               
               
                 CFB02 
                 UCUGUCUGAUCCAUCUAGCGAUGGAUCAGACAGA 
               
               
                   
               
               
                 CFB03 
                 UACCAUGCCACAGAGACUCCUCUGUGGCAUGGUA 
               
               
                   
               
               
                 CFB04 
                 UAUCCAUCUAGCACCAGGUGGUGCUAGAUGGAUA 
               
               
                   
               
               
                 CFB05 
                 UAAACCCAAAUCCUCAUCUGAGGAUUUGGGUUUA 
               
               
                   
               
               
                 CFB06 
                 UCCAUCUAGCACCAGGUAGCUGGUGCUAGAUGGA 
               
               
                   
               
               
                 CFB07 
                 UAAAACCCAAAUCCUCAUCAGGAUUUGGGUUUUA 
               
               
                   
               
               
                 CFB08 
                 UGUCUGAUCCAUCUAGCACUAGAUGGAUCAGACA 
               
               
                   
               
               
                 CFB09 
                 UACCCAAAUCCUCAUCUUGAUGAGGAUUUGGGUA 
               
               
                   
               
               
                 CFB10 
                 UUCCAUCUAGCACCAGGUAUGGUGCUAGAUGGAA 
               
               
                   
               
               
                 CFB11 
                 UAACCCAAAUCCUCAUCUUUGAGGAUUUGGGUUA 
               
               
                   
               
               
                 CFB12 
                 UCAUGCCACAGAGACUCAGGUCUCUGUGGCAUGA 
               
               
                   
               
               
                 CFB13 
                 UUGCCACAGAGACUCAGAGGAGUCUCUGUGGCAA 
               
               
                   
               
               
                 CFB14 
                 UAUGAUGACAUGGCGGGUGCGCCAUGUCAUCAUA 
               
               
                   
               
               
                 CFB15 
                 UUCCAUAUCCUUGACUUUGGUCAAGGAUAUGGAA 
               
               
                   
               
               
                 CFB16 
                 UACACCAACUUGAAUGAAAAUUCAAGUUGGUGUA 
               
               
                   
               
               
                 CFB17 
                 UGCCACAGAGACUCAGAGAUGAGUCUCUGUGGCA 
               
               
                   
               
               
                 CFB18 
                 UCCAUGCCACAGAGACUCAUCUCUGUGGCAUGGA 
               
               
                   
               
               
                 CFB19 
                 UCAUCUAGCACCAGGUAGACCUGGUGCUAGAUGA 
               
               
                   
               
               
                 CFB20 
                 UUUCCAUAUCCUUGACUUUUCAAGGAUAUGGAAA 
               
               
                   
               
               
                 CFB21 
                 UGAUCCAUCUAGCACCAGGGUGCUAGAUGGAUCA 
               
               
                   
               
               
                 CFB22 
                 UCCACAGAGACUCAGAGACCUGAGUCUCUGUGGA 
               
               
                   
               
               
                 CFB23 
                 UUGAUCCAUCUAGCACCAGUGCUAGAUGGAUCAA 
               
               
                   
               
               
                 CFB24 
                 UACCUCCUUCCGAGUCAGCACUCGGAAGGAGGUA 
               
               
                   
               
               
                 CFB25 
                 UUCUGAUCCAUCUAGCACCCUAGAUGGAUCAGAA 
               
               
                   
               
               
                 CFB26 
                 UUCUUGGCAGGAAGGCUCCCCUUCCUGCCAAGAA 
               
               
                   
               
               
                 CFB27 
                 UUCUAGCACCAGGUAGAUGUACCUGGUGCUAGAA 
               
               
                   
               
               
                 CFB28 
                 UAAGUACUCAGACACCACAGUGUCUGAGUACUUA 
               
               
                   
               
               
                 CFB29 
                 UUGUCUGAUCCAUCUAGCAAGAUGGAUCAGACAA 
               
               
                   
               
               
                 CFB30 
                 UAUCUAGCACCAGGUAGAUACCUGGUGCUAGAUA 
               
               
                   
               
               
                 CFB31 
                 UCAAAUCCUCAUCUUGGAGAAGAUGAGGAUUUGA 
               
               
                   
               
               
                 CFB32 
                 UAUAGUCAUAAAAUUCAGGAAUUUUAUGACUAUA 
               
               
                   
               
               
                 CFB33 
                 UAGGAUGAUGACAUGGCGGCAUGUCAUCAUCCUA 
               
               
                   
               
               
                 CFB34 
                 UCAAUCUGUGUUCUGGCACCAGAACACAGAUUGA 
               
               
                   
               
               
                 CFB35 
                 UUGAGCUUGAUCAGGGCAACCUGAUCAAGCUCAA 
               
               
                   
               
               
                 CFB36 
                 UAGUGGAAAGAGAUCUCAUGAUCUCUUUCCACUA 
               
               
                   
               
               
                 CFB37 
                 UAGAUGUUCAUGGAGCCUGCUCCAUGAACAUCUA 
               
               
                   
               
               
                 CFB38 
                 UGCAAGUGGUAGUUGGAGGCAACUACCACUUGCA 
               
               
                   
               
               
                 CFB39 
                 UCACACCAUAACUUGCCACCAAGUUAUGGUGUGA 
               
               
                   
               
               
                 CFB40 
                 UAAAGAGAUCUCAUCACUCGAUGAGAUCUCUUUA 
               
               
                   
               
               
                 CFB41 
                 UUCAACUUGUGGUCUUCAUAGACCACAAGUUGAA 
               
               
                   
               
               
                 CFB42 
                 UAAACGACUUCUCUUGUGAAAGAGAAGUCGUUUA 
               
               
                   
               
               
                 CFB43 
                 UGUAUGUGGCAUAUGUCACCAUAUGCCACAUACA 
               
               
                   
               
               
                 CFB44 
                 UGUCUUUCUUGGAAGCCAACUUCCAAGAAAGACA 
               
               
                   
               
               
                 CFB45 
                 UCAUCCAGAUAAUCCUCCCGGAUUAUCUGGAUGA 
               
               
                   
               
               
                 CFB46 
                 UUUGACUUUGUCAUAGCCUUAUGACAAAGUCAAA 
               
               
                   
               
               
                 CFB47 
                 UAAACUCCAGACCUAGACCUAGGUCUGGAGUUUA 
               
               
                   
               
               
                 CFB48 
                 UAUAACUUGCCACCUUCUCAGGUGGCAAGUUAUA 
               
               
                   
               
               
                 CFB49 
                 UCAUAGUCAUAAAAUUCAGAUUUUAUGACUAUGA 
               
               
                   
               
               
                 CFB50 
                 UUGGCUCCUGUGAAGUUGCCUUCACAGGAGCCAA 
               
               
                   
               
               
                 CFB51 
                 UAAAGUACUCAGACACCACUGUCUGAGUACUUUA 
               
               
                   
               
               
                 CFB52 
                 UGCUCAUUGUCUUUCUUGGGAAAGACAAUGAGCA 
               
               
                   
               
               
                 CFB53 
                 UUAAAAUUCAGGAAUUCCUAUUCCUGAAUUUUAA 
               
               
                   
               
               
                 CFB54 
                 UGAGAUCUUGGCCUGCCAUCAGGCCAAGAUCUCA 
               
               
                   
               
               
                 CFB55 
                 UGAGCAUCUCUCUCACAGCUGAGAGAGAUGCUCA 
               
               
                   
               
               
                 CFB56 
                 UAACCGUCAUAGCAGUGGACUGCUAUGACGGUUA 
               
               
                   
               
               
                 CFB57 
                 UAGAGCUUUGAUAUCCUGUGAUAUCAAAGCUCUA 
               
               
                   
               
               
                 CFB58 
                 UACAAUGUGCUGCUGUCAGCAGCAGCACAUUGUA 
               
               
                   
               
               
                 CFB59 
                 UGGUACGGGUAGAAGCCAGCUUCUACCCGUACCA 
               
               
                   
               
               
                 CFB60 
                 UCAGACCUAGACCUGGUCACAGGUCUAGGUCUGA 
               
               
                   
               
               
                 CFB61 
                 UUUCUCUUGUGAACUAUCAAGUUCACAAGAGAAA 
               
               
                   
               
               
                 CFB62 
                 UUUCAGGAAUUCCUGCUUCCAGGAAUUCCUGAAA 
               
               
                   
               
               
                 CFB63 
                 UCCAGGUUUUCCAUAUCCUUAUGGAAAACCUGGA 
               
               
                   
               
               
                 CFB64 
                 UCAACUUGAAUGAAACGACUUUCAUUCAAGUUGA 
               
               
                   
               
               
                 CFB65 
                 UGUGCUGCUGUCAGCACAAGCUGACAGCAGCACA 
               
               
                   
               
               
                 CFB66 
                 UGACCUCCUUCCGAGUCAGCUCGGAAGGAGGUCA 
               
               
                   
               
               
                 CFB67 
                 UCAAUUAAGUUGACUAGACAGUCAACUUAAUUGA 
               
               
                   
               
               
                 CFB68 
                 UUGACACGUUCGCCGCUGGCGGCGAACGUGUCAA 
               
               
                   
               
               
                 CFB69 
                 UCAUUGUCUUUCUUGGAAGCAAGAAAGACAAUGA 
               
               
                   
               
               
                 CFB70 
                 UCCAACUUGAAUGAAACGAUUCAUUCAAGUUGGA 
               
               
                   
               
               
                 CFB71 
                 UCACAAAGUACUCAGACACCUGAGUACUUUGUGA 
               
               
                   
               
               
                 CFB72 
                 UUGCAGUGGUAGGUGACGCCACCUACCACUGCAA 
               
               
                   
               
               
                 CFB73 
                 UUCAUGAGGAUGAUGACAUCAUCAUCCUCAUGAA 
               
               
                   
               
               
                 CFB74 
                 UUUCAACUUGUGGUCUUCAGACCACAAGUUGAAA 
               
               
                   
               
               
                 CFB75 
                 UGUAGUUGGAGGAAGCCUCCUUCCUCCAACUACA 
               
               
                   
               
               
                 CFB76 
                 UCAUGCUGUACACUGCCUGCAGUGUACAGCAUGA 
               
               
                   
               
               
                 CFB77 
                 UUGUCUUUCUUGGAAGCCAUUCCAAGAAAGACAA 
               
               
                   
               
               
                 CFB78 
                 UCGACUCCUUCUAUGGUCUCAUAGAAGGAGUCGA 
               
               
                   
               
               
                 CFB79 
                 UGACAUCCAGAUAAUCCUCAUUAUCUGGAUGUCA 
               
               
                   
               
               
                 CFB80 
                 UUGAGAUCUUGGCCUGCCAAGGCCAAGAUCUCAA 
               
               
                   
               
               
                 CFB81 
                 UACGCUGUCUUCAAGGCGGCUUGAAGACAGCGUA 
               
               
                   
               
               
                 CFB82 
                 UAGACAGGAAAGCUUCGGCAAGCUUUCCUGUCUA 
               
               
                   
               
               
                 CFB83 
                 UUUGAACACAUGUUGCUCACAACAUGUGUUCAAA 
               
               
                   
               
               
                 CFB84 
                 UAUAAAAUUCAGGAAUUCCUUCCUGAAUUUUAUA 
               
               
                   
               
               
                 CFB85 
                 UCCCAAAUCCUCAUCUUGGGAUGAGGAUUUGGGA 
               
               
                   
               
               
                 CFB86 
                 UAAGAGAUCUCAUCACUCAUGAUGAGAUCUCUUA 
               
               
                   
               
               
                 CFB87 
                 UAAAGCAUUGAUGUUCACUAACAUCAAUGCUUUA 
               
               
                   
               
               
                 CFB88 
                 UAGGAAUUCCUGCUUCUUUAAGCAGGAAUUCCUA 
               
               
                   
               
               
                 CFB89 
                 UAUGAAGGAGUCUUGGCAGCAAGACUCCUUCAUA 
               
               
                   
               
               
                 CFB90 
                 UAAGCUUCGGCCACCUCUUGGUGGCCGAAGCUUA 
               
               
                   
               
               
                 CFB91 
                 UUGACUUUGUCAUAGCCUGCUAUGACAAAGUCAA 
               
               
                   
               
               
                 CFB92 
                 UUCCAAGCUGAAACUCCAGAGUUUCAGCUUGGAA 
               
               
                   
               
               
                 CFB93 
                 UCCAAAUCCUCAUCUUGGAAGAUGAGGAUUUGGA 
               
               
                   
               
               
                 CFB94 
                 UCAGCUGUUUUAAUUCAAUAAUUAAAACAGCUGA 
               
               
                   
               
               
                 CFB95 
                 UAACGACUUCUCUUGUGAACAAGAGAAGUCGUUA 
               
               
                   
               
               
                 CFB96 
                 UCCGGAACAUCCAAGCGGGCUUGGAUGUUCCGGA 
               
               
                   
               
               
                 CFB97 
                 UCAAACACAUAGACAUCCAUGUCUAUGUGUUUGA 
               
               
                   
               
               
                 CFB98 
                 UUUCACACCAUAACUUGCCAGUUAUGGUGUGAAA 
               
               
                   
               
               
                 CFB99 
                 UUCUCUUGUGAACUAUCAAUAGUUCACAAGAGAA 
               
               
                   
               
               
                 CFB100 
                 UAUUCAGGAAUUCCUGCUUAGGAAUUCCUGAAUA 
               
               
                   
               
               
                 CFB101 
                 UGACACUUUGACCCAAAUUUGGGUCAAAGUGUCA 
               
               
                   
               
               
                 CFB102 
                 UCACAAACAGAGCUUUGAUAAGCUCUGUUUGUGA 
               
               
                   
               
               
                 CFB103 
                 UCAAACAGAGCUUUGAUAUCAAAGCUCUGUUUGA 
               
               
                   
               
               
                 CFB104 
                 UUUGGAGUUUCUCCUUCAGAGGAGAAACUCCAAA 
               
               
                   
               
               
                 CFB105 
                 UUCACACCAUAACUUGCCAAAGUUAUGGUGUGAA 
               
               
                   
               
               
                 CFB106 
                 UUGAAUGAAACGACUUCUCAGUCGUUUCAUUCAA 
               
               
                   
               
               
                 CFB107 
                 UCAGGUUUUCCAUAUCCUUAUAUGGAAAACCUGA 
               
               
                   
               
               
                 CFB108 
                 UGCAUCUCUCUCACAGCUGUGUGAGAGAGAUGCA 
               
               
                   
               
               
                 CFB109 
                 UACAUCCAGAUAAUCCUCCGAUUAUCUGGAUGUA 
               
               
                   
               
               
                 CFB110 
                 UCGAGUUGUUCCCUCGGUGGAGGGAACAACUCGA 
               
               
                   
               
               
                 CFB111 
                 UACACAUGUUGCUCAUUGUUGAGCAACAUGUGUA 
               
               
                   
               
               
                 CFB112 
                 UUCUCAAUUAAGUUGACUACAACUUAAUUGAGAA 
               
               
                   
               
               
                 CFB113 
                 UGAAGCCAAAGCAUUGAUGAAUGCUUUGGCUUCA 
               
               
                   
               
               
                 CFB114 
                 UGCAGUGGAAAGAGAUCUCUCUCUUUCCACUGCA 
               
               
                   
               
               
                 CFB115 
                 UACACUGCCUGGAGGGCCUCCUCCAGGCAGUGUA 
               
               
                   
               
               
                 CFB116 
                 UUAGACCUGGUCACAUUCCUGUGACCAGGUCUAA 
               
               
                   
               
               
                 CFB117 
                 UCAGACACAAACAGAGCUUUCUGUUUGUGUCUGA 
               
               
                   
               
               
                 CFB118 
                 UGAGUUUCUCCUUCAGCCAUGAAGGAGAAACUCA 
               
               
                   
               
               
                 CFB119 
                 UAUGUGCUGCUGUCAGCACUGACAGCAGCACAUA 
               
               
                   
               
               
                 CFB120 
                 UCAGAGCUUUGAUAUCCUGAUAUCAAAGCUCUGA 
               
               
                   
               
               
                 CFB121 
                 UGAUAUCCUGUGCAGGGAGCUGCACAGGAUAUCA 
               
               
                   
               
               
                 CFB122 
                 UAGGGCAACGUCAUAGUCAUAUGACGUUGCCCUA 
               
               
                   
               
               
                 CFB123 
                 UAGACCUAGACCUGGUCACCCAGGUCUAGGUCUA 
               
               
                   
               
               
                 CFB124 
                 UAGUACUCAGACACCACAGGGUGUCUGAGUACUA 
               
               
                   
               
               
                 CFB125 
                 UAAGGCUCCGUCCCGCUCCCGGGACGGAGCCUUA 
               
               
                   
               
               
                 CFB126 
                 UGGGCAACGUCAUAGUCAUCUAUGACGUUGCCCA 
               
               
                   
               
               
                 CFB127 
                 UCUGUUUUAAUUCAAUCCCUUGAAUUAAAACAGA 
               
               
                   
               
               
                 CFB128 
                 UAGAGAUCUCAUCACUCACGUGAUGAGAUCUCUA 
               
               
                   
               
               
                 CFB129 
                 UGGUCUUCAUAAUUGAUUUCAAUUAUGAAGACCA 
               
               
                   
               
               
                 CFB130 
                 UCAUAUCUUGGCUUCACACGAAGCCAAGAUAUGA 
               
               
                   
               
               
                 CFB131 
                 UCACCAACUUGAAUGAAACCAUUCAAGUUGGUGA 
               
               
                   
               
               
                 CFB132 
                 UAGCUGUUUUAAUUCAAUCGAAUUAAAACAGCUA 
               
               
                   
               
               
                 CFB133 
                 UUAACUUGCCACCUUCUCAAAGGUGGCAAGUUAA 
               
               
                   
               
               
                 CFB134 
                 UUGAGCAGGUACCUGCUUUCAGGUACCUGCUCAA 
               
               
                   
               
               
                 CFB135 
                 UUUGAUGUAGACCUCCUUCGAGGUCUACAUCAAA 
               
               
                   
               
               
                 CFB136 
                 UGGCAAGUGGUAGUUGGAGAACUACCACUUGCCA 
               
               
                   
               
               
                 CFB137 
                 UGGAAGCCUCAAAGCUCGAGCUUUGAGGCUUCCA 
               
               
                   
               
               
                 CFB138 
                 UAAUGACAGUAAUUGGGUCCAAUUACUGUCAUUA 
               
               
                   
               
               
                 CFB139 
                 UUUUGAACACAUGUUGCUCAACAUGUGUUCAAAA 
               
               
                   
               
               
                 CFB140 
                 UAAAUCCUCAUCUUGGAGUCAAGAUGAGGAUUUA 
               
               
                   
               
               
                 CFB141 
                 UGGAGUUUCUCCUUCAGCCGAAGGAGAAACUCCA 
               
               
                   
               
               
                 CFB142 
                 UCAUAACUUGCCACCUUCUGGUGGCAAGUUAUGA 
               
               
                   
               
               
                 CFB143 
                 UGCUGUUUUAAUUCAAUCCUGAAUUAAAACAGCA 
               
               
                   
               
               
                 CFB144 
                 UAAGCUCGAGUUGUUCCCUAACAACUCGAGCUUA 
               
               
                   
               
               
                 CFB145 
                 UGGCAACGUCAUAGUCAUAACUAUGACGUUGCCA 
               
               
                   
               
               
                 CFB146 
                 UUUCCAGGUUUUCCAUAUCUGGAAAACCUGGAAA 
               
               
                   
               
               
                 CFB147 
                 UUCCAGGUUUUCCAUAUCCAUGGAAAACCUGGAA 
               
               
                   
               
               
                 CFB148 
                 UCCAUGUUGUGCAAUCCAUAUUGCACAACAUGGA 
               
               
                   
               
               
                 CFB149 
                 UCAUAUCCUUGACUUUGAAAAGUCAAGGAUAUGA 
               
               
                   
               
               
                 CFB150 
                 UUGACUUUGAACACAUGUUUGUGUUCAAAGUCAA 
               
               
                   
               
               
                 CFB151 
                 UCUCAUCUUGGAGUUUCUCAACUCCAAGAUGAGA 
               
               
                   
               
               
                 CFB152 
                 UCAUGUUGCUCAUUGUCUUCAAUGAGCAACAUGA 
               
               
                   
               
               
                 CFB153 
                 UACCAACUUGAAUGAAACGUCAUUCAAGUUGGUA 
               
               
                   
               
               
                 CFB154 
                 UACAGAUCGCUGUCUGCCCAGACAGCGAUCUGUA 
               
               
                   
               
               
                 CFB155 
                 UUCACAGCUGCCUUUCUUAAAAGGCAGCUGUGAA 
               
               
                   
               
               
                 CFB156 
                 UGGCCGCCAGAAUCACCUCUGAUUCUGGCGGCCA 
               
               
                   
               
               
                 CFB157 
                 UCCAAGCUGAAACUCCAGAGAGUUUCAGCUUGGA 
               
               
                   
               
               
                 CFB158 
                 UUUGAUCAGGGCAACGUCAGUUGCCCUGAUCAAA 
               
               
                   
               
               
                 CFB159 
                 UGUUCCCAAACCAUGCCACCAUGGUUUGGGAACA 
               
               
                   
               
               
                 CFB160 
                 UACCUGCUUUUGCCGCUUCCGGCAAAAGCAGGUA 
               
               
                   
               
               
                 CFB161 
                 UUUGCUCAUUGUCUUUCUUAAGACAAUGAGCAAA 
               
               
                   
               
               
                 CFB162 
                 UCACGUUCGCCGCUGGGAGCAGCGGCGAACGUGA 
               
               
                   
               
               
                 CFB163 
                 UCAUUCUUGAUGUAGACCUCUACAUCAAGAAUGA 
               
               
                   
               
               
                 CFB164 
                 UUUGAGCUUGAUCAGGGCACUGAUCAAGCUCAAA 
               
               
                   
               
               
                 CFB165 
                 UAUUCUUGAUGUAGACCUCUCUACAUCAAGAAUA 
               
               
                   
               
               
                 CFB166 
                 UUGAAGGAGUCUUGGCAGGCCAAGACUCCUUCAA 
               
               
                   
               
               
                 CFB167 
                 UUUGGCUUCACACCAUAACUGGUGUGAAGCCAAA 
               
               
                   
               
               
                 CFB168 
                 UAUCUUGGCUUCACACCAUUGUGAAGCCAAGAUA 
               
               
                   
               
               
                 CFB169 
                 UCUCACAGCUGCCUUUCUUAAGGCAGCUGUGAGA 
               
               
                   
               
               
                 CFB170 
                 UCCAAUGCUGUCUGAUCCAUCAGACAGCAUUGGA 
               
               
                   
               
               
                 CFB171 
                 UGAGUGGUGGUCACACCUCUGUGACCACCACUCA 
               
               
                   
               
               
                 CFB172 
                 UAUAGGGACUCACUCCUCCGAGUGAGUCCCUAUA 
               
               
                   
               
               
                 CFB173 
                 UCUGACUUCAACUUGUGGUCAAGUUGAAGUCAGA 
               
               
                   
               
               
                 CFB174 
                 UUUCUCAAUUAAGUUGACUAACUUAAUUGAGAAA 
               
               
                   
               
               
                 CFB175 
                 UAGUUUCUCCUUCAGCCAGCUGAAGGAGAAACUA 
               
               
                   
               
               
                 CFB176 
                 UAGCUUUGAUAUCCUGUGCAGGAUAUCAAAGCUA 
               
               
                   
               
               
                 CFB177 
                 UUGUCCUUGACUUUGUCAUCAAAGUCAAGGACAA 
               
               
                   
               
               
                 CFB178 
                 UCAGGUACGUGUCUGCACACAGACACGUACCUGA 
               
               
                   
               
               
                 CFB179 
                 UAAACAAUGUGCUGCUGUCGCAGCACAUUGUUUA 
               
               
                   
               
               
                 CFB180 
                 UAUAUCCUGUGCAGGGAGCCCUGCACAGGAUAUA 
               
               
                   
               
               
                 CFB181 
                 UGACUCAGAGACUGGCUUUCCAGUCUCUGAGUCA 
               
               
                   
               
               
                 CFB182 
                 UCAAUGACAGUAAUUGGGUAAUUACUGUCAUUGA 
               
               
                   
               
               
                 CFB183 
                 UGAGCCACCUUCCUGACACCAGGAAGGUGGCUCA 
               
               
                   
               
               
                 CFB184 
                 UCUUGACUUUGAACACAUGUGUUCAAAGUCAAGA 
               
               
                   
               
               
                 CFB185 
                 UAUGAAACGACUUCUCUUGAGAAGUCGUUUCAUA 
               
               
                   
               
               
                 CFB186 
                 UGAAGACAGGAAAGCUUCGGCUUUCCUGUCUUCA 
               
               
                   
               
               
                 CFB187 
                 UGCUUUGAUAUCCUGUGCACAGGAUAUCAAAGCA 
               
               
                   
               
               
                 CFB188 
                 UUCUUGAGCUUGAUCAGGGGAUCAAGCUCAAGAA 
               
               
                   
               
               
                 CFB189 
                 UGGAUUGCUCUGCACUCUGGUGCAGAGCAAUCCA 
               
               
                   
               
               
                 CFB190 
                 UCAUAUUGAGCAUCUCUCUAGAUGCUCAAUAUGA 
               
               
                   
               
               
                 CFB191 
                 UAUCCUUGACUUUGAACACUCAAAGUCAAGGAUA 
               
               
                   
               
               
                 CFB192 
                 UGCAGACAUCCACUACUCCUAGUGGAUGUCUGCA 
               
               
                   
               
               
                 CFB193 
                 UAGACCUCCUUCCGAGUCAUCGGAAGGAGGUCUA 
               
               
                   
               
               
                 CFB194 
                 UACCUUCUCAAUUAAGUUGUUAAUUGAGAAGGUA 
               
               
                   
               
               
                 CFB195 
                 UAGAAGUCGGAAGGAGCCGUCCUUCCGACUUCUA 
               
               
                   
               
               
                 CFB196 
                 UUGCACAGGGUACGGGUAGCCGUACCCUGUGCAA 
               
               
                   
               
               
                 CFB197 
                 UAUGACAGUAAUUGGGUCCCCAAUUACUGUCAUA 
               
               
                   
               
               
                 CFB198 
                 UGUUAGUCCCUGACUUCAAAGUCAGGGACUAACA 
               
               
                   
               
               
                 CFB199 
                 UAUAUCCUUGACUUUGAACAAAGUCAAGGAUAUA 
               
               
                   
               
               
                 CFB200 
                 UGUACGUGUCUGCACAGGGGUGCAGACACGUACA 
               
               
                   
               
               
                 CFB201 
                 UGUCAGCACAAAGUACUCAUACUUUGUGCUGACA 
               
               
                   
               
               
                 CFB202 
                 UUGGUCUUCAUAAUUGAUUAAUUAUGAAGACCAA 
               
               
                   
               
               
                 CFB203 
                 UCAGAGACUCAGAGACUGGUCUCUGAGUCUCUGA 
               
               
                   
               
               
                 CFB204 
                 UUAGACAUCCAGAUAAUCCUAUCUGGAUGUCUAA 
               
               
                   
               
               
                 CFB205 
                 UCUCCUUCCGAGUCAGCUUUGACUCGGAAGGAGA 
               
               
                   
               
               
                 CFB206 
                 UCAUGGAGCCUGAAGGGUCCUUCAGGCUCCAUGA 
               
               
                   
               
               
                 CFB207 
                 UUGGCAUAUGUCACUAGACAGUGACAUAUGCCAA 
               
               
                   
               
               
                 CFB208 
                 UAAGCAUUGAUGUUCACUUGAACAUCAAUGCUUA 
               
               
                   
               
               
                 CFB209 
                 UCUCACUCCUCCAGUACAAACUGGAGGAGUGAGA 
               
               
                   
               
               
                 CFB210 
                 UGAUGUCCUUGACUUUGUCAAGUCAAGGACAUCA 
               
               
                   
               
               
                 CFB211 
                 UUGUUUUAAUUCAAUCCCAAUUGAAUUAAAACAA 
               
               
                   
               
               
                 CFB212 
                 UUAGAUGUUCAUGGAGCCUUCCAUGAACAUCUAA 
               
               
                   
               
               
                 CFB213 
                 UAUAGCAGUGGAAAGAGAUCUUUCCACUGCUAUA 
               
               
                   
               
               
                 CFB214 
                 UCAUUCACUUGGCAGGUGCCUGCCAAGUGAAUGA 
               
               
                   
               
               
                 CFB215 
                 UAUUGAUGUUCACUUGGUUAAGUGAACAUCAAUA 
               
               
                   
               
               
                 CFB216 
                 UCAGCCAGGGCAGCACUUGUGCUGCCCUGGCUGA 
               
               
                   
               
               
                 CFB217 
                 UCUCAGUGUCCAAGCUGAAGCUUGGACACUGAGA 
               
               
                   
               
               
                 CFB218 
                 UCAGAGACUGGCUUUCAUCAAAGCCAGUCUCUGA 
               
               
                   
               
               
                 CFB219 
                 UAUCCAGAUAAUCCUCCCUAGGAUUAUCUGGAUA 
               
               
                   
               
               
                 CFB220 
                 UCUUCUCAAUUAAGUUGACACUUAAUUGAGAAGA 
               
               
                   
               
               
                 CFB221 
                 UCCAGACCUAGACCUGGUCAGGUCUAGGUCUGGA 
               
               
                   
               
               
                 CFB222 
                 UCAACGUCAUAGUCAUAAAUGACUAUGACGUUGA 
               
               
                   
               
               
                 CFB223 
                 UUUGAAUGAAACGACUUCUGUCGUUUCAUUCAAA 
               
               
                   
               
               
                 CFB224 
                 UCCUCCUCAGACACAAACAUGUGUCUGAGGAGGA 
               
               
                   
               
               
                 CFB225 
                 UAAGCCAAAGCAUUGAUGUCAAUGCUUUGGCUUA 
               
               
                   
               
               
                 CFB226 
                 UUGAAACGACUUCUCUUGUGAGAAGUCGUUUCAA 
               
               
                   
               
               
                 CFB227 
                 UAACUUGUGGUCUUCAUAAGAAGACCACAAGUUA 
               
               
                   
               
               
                 CFB228 
                 UCCAGGUAGAUGUUCAUGGGAACAUCUACCUGGA 
               
               
                   
               
               
                 CFB229 
                 UCUGUGUUCUGGCACCUGCGUGCCAGAACACAGA 
               
               
                   
               
               
                 CFB230 
                 UAACUUGCCACCUUCUCAAGAAGGUGGCAAGUUA 
               
               
                   
               
               
                 CFB231 
                 UGCCAUGGUUGCUUGUGGUCAAGCAACCAUGGCA 
               
               
                   
               
               
                 CFB232 
                 UGACAAAUGGGCCUGAUAGCAGGCCCAUUUGUCA 
               
               
                   
               
               
                 CFB233 
                 UAAGUUGACUAGACACUUUUGUCUAGUCAACUUA 
               
               
                   
               
               
                 CFB234 
                 UCAUGGCGGGUGCGGUUCCCCGCACCCGCCAUGA 
               
               
                   
               
               
                 CFB235 
                 UCCGGAUCUCAUCAAUGACUUGAUGAGAUCCGGA 
               
               
                   
               
               
                 CFB236 
                 UGAGGAAGCCUCAAAGCUCUUUGAGGCUUCCUCA 
               
               
                   
               
               
                 CFB237 
                 UACUUUGAACACAUGUUGCCAUGUGUUCAAAGUA 
               
               
                   
               
               
                 CFB238 
                 UCUCCUCCUCAGACACAAAUGUCUGAGGAGGAGA 
               
               
                   
               
               
                 CFB239 
                 UAGGAAGGCUCCGUCCCGCGACGGAGCCUUCCUA 
               
               
                   
               
               
                 CFB240 
                 UCGCCAGAAUCACCUCUGCAGGUGAUUCUGGCGA 
               
               
                   
               
               
                 CFB241 
                 UGGAAAGAGAUCUCAUCACUGAGAUCUCUUUCCA 
               
               
                   
               
               
                 CFB242 
                 UAAGUCCCGGAUCUCAUCAGAGAUCCGGGACUUA 
               
               
                   
               
               
                 CFB243 
                 UGAGCUUGAUCAGGGCAACCCCUGAUCAAGCUCA 
               
               
                   
               
               
                 CFB244 
                 UGUUGCUCAUUGUCUUUCUAGACAAUGAGCAACA 
               
               
                   
               
               
                 CFB245 
                 UUGCUUGUGGUAAUCGGUAGAUUACCACAAGCAA 
               
               
                   
               
               
                 CFB246 
                 UUCAUCACUCACAUUGUAGAAUGUGAGUGAUGAA 
               
               
                   
               
               
                 CFB247 
                 UCAGUGUCCAAGCUGAAACCAGCUUGGACACUGA 
               
               
                   
               
               
                 CFB248 
                 UCCAUUCUUGAUGUAGACCUACAUCAAGAAUGGA 
               
               
                   
               
               
                 CFB249 
                 UAACAAUGUGCUGCUGUCAAGCAGCACAUUGUUA 
               
               
                   
               
               
                 CFB250 
                 UGACUUCAACUUGUGGUCUCACAAGUUGAAGUCA 
               
               
                   
               
               
                 13(5) as + s 
                 UUGCCACAGAGACUCAGAGAGUCUCUGUGGCAA 
               
               
                   
               
               
                 106-13(4) 
                 UUGAAUGAAACGACUUCUCGUUUCAUUCAA 
               
               
                 as + s 
               
               
                   
               
            
           
         
       
     
     Table 3 below shows 252 hairpins with full modification information (modified sugars and, where applicable, modified phosphates). 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Modified hairpin constructs 
               
            
           
           
               
               
            
               
                 # 
                   
               
               
                   
               
            
           
           
               
               
            
               
                   1 
                 PmU.fA.mG.mA.mA.mA.mA.mC.mC.mC.mA.mA.mA.fU.mC.mC.mU.mC.mA.mG.mA.fU.fU.fU.mG.mG.mG. 
               
               
                   
                 mU.mU.mU.mU.mC.mU.mA 
               
               
                   
               
               
                   2 
                 PmU.fC.mU.mG.mU.mC.mU.mG.mA.mU.mC.mC.mA.fU.mC.mU.mA.mG.mC.mG.mA.fU.fG.fG.mA.mU.mC. 
               
               
                   
                 mA.mG.mA.mC.mA.mG.mA 
               
               
                   
               
               
                   3 
                 PmU.fA.mC.mC.mA.mU.mG.mC.mC.mA.mC.mA.mG.fA.mG.mA.mC.mU.mC.mC.mU.fC.fU.fG.mU.mG.mG. 
               
               
                   
                 mC.mA.mU.mG.mG.mU.mA 
               
               
                   
               
               
                   4 
                 PmU.fA.mU.mC.mC.mA.mU.mC.mU.mA.mG.mC.mA.fC.mC.mA.mG.mG.mU.mG.mG.fU.fG.fC.mU.mA.mG. 
               
               
                   
                 mA.mU.mG.mG.mA.mU.mA 
               
               
                   
               
               
                   5 
                 PmU.fA.mA.mA.mC.mC.mC.mA.mA.mA.mU.mC.mC.fU.mC.mA.mU.mC.mU.mG.mA.fG.fG.fA.mU.mU.mU. 
               
               
                   
                 mG.mG.mG.mU.mU.mU.mA 
               
               
                   
               
               
                   6 
                 PmU.fC.mC.mA.mU.mC.mU.mA.mG.mC.mA.mC.mC.fA.mG.mG.mU.mA.mG.mC.mU.fG.fG.fU.mG.mC.mU. 
               
               
                   
                 mA.mG.mA.mU.mG.mG.mA 
               
               
                   
               
               
                   7 
                 PmU.fA.mA.mA.mA.mC.mC.mC.mA.mA.mA.mU.mC.fC.mU.mC.mA.mU.mC.mA.mG.fG.fA.fU.mU.mU.mG. 
               
               
                   
                 mG.mG.mU.mU.mU.mU.mA 
               
               
                   
               
               
                   8 
                 PmU.fG.mU.mC.mU.mG.mA.mU.mC.mC.mA.mU.mC.fU.mA.mG.mC.mA.mC.mU.mA.fG.fA.fU.mG.mG.mA. 
               
               
                   
                 mU.mC.mA.mG.mA.mC.mA 
               
               
                   
               
               
                   9 
                 PmU.fA.mC.mC.mC.mA.mA.mA.mU.mC.mC.mU.mC.fA.mU.mC.mU.mU.mG.mA.mU.fG.fA.fG.mG.mA.mU. 
               
               
                   
                 mU.mU.mG.mG.mG.mU.mA 
               
               
                   
               
               
                  10 
                 PmU.fU.mC.mC.mA.mU.mC.mU.mA.mG.mC.mA.mC.fC.mA.mG.mG.mU.mA.mU.mG.fG.fU.fG.mC.mU.mA. 
               
               
                   
                 mG.mA.mU.mG.mG.mA.mA 
               
               
                   
               
               
                  11 
                 PmU.fA.mA.mC.mC.mC.mA.mA.mA.mU.mC.mC.mU.fC.mA.mU.mC.mU.mU.mU.mG.fA.fG.fG.mA.mU.mU. 
               
               
                   
                 mU.mG.mG.mG.mU.mU.mA 
               
               
                   
               
               
                  12 
                 PmU.fC.mA.mU.mG.mC.mC.mA.mC.mA.mG.mA.mG.fA.mC.mU.mC.mA.mG.mG.mU.fC.fU.fC.mU.mG.mU. 
               
               
                   
                 mG.mG.mC.mA.mU.mG.mA 
               
               
                   
               
               
                  13 
                 PmU.fU.mG.mC.mC.mA.mC.mA.mG.mA.mG.mA.mC.fU.mC.mA.mG.mA.mG.mG.mA.fG.fU.fC.mU.mC.mU. 
               
               
                   
                 mG.mU.mG.mG.mC.mA.mA 
               
               
                   
               
               
                  14 
                 PmU.fA.mU.mG.mA.mU.mG.mA.mC.mA.mU.mG.mG.fC.mG.mG.mG.mU.mG.mC.mG.fC.fC.fA.mU.mG.mU. 
               
               
                   
                 mC.mA.mU.mC.mA.mU.mA 
               
               
                   
               
               
                  15 
                 PmU.fU.mC.mC.mA.mU.mA.mU.mC.mC.mU.mU.mG.fA.mC.mU.mU.mU.mG.mG.mU.fC.fA.fA.mG.mG.mA. 
               
               
                   
                 mU.mA.mU.mG.mG.mA.mA 
               
               
                   
               
               
                  16 
                 PmU.fA.mC.mA.mC.mC.mA.mA.mC.mU.mU.mG.mA.fA.mU.mG.mA.mA.mA.mA.mU.fU.fC.fA.mA.mG.mU 
               
               
                   
                 mU.mG.mG.mU.mG.mU.mA 
               
               
                   
               
               
                  17 
                 PmU.fG.mC.mC.mA.mC.mA.mG.mA.mG.mA.mC.mU.fC.mA.mG.mA.mG.mA.mU.mG.fA.fG.fU.mC.mU.mC. 
               
               
                   
                 mU.mG.mU.mG.mG.mC.mA 
               
               
                   
               
               
                  18 
                 PmU.fC.mC.mA.mU.mG.mC.mC.mA.mC.mA.mG.mA.fG.mA.mC.mU.mC.mA.mU.mC.fU.fC.fU.mG.mU.mG. 
               
               
                   
                 mG.mC.mA.mU.mG.mG.mA 
               
               
                   
               
               
                  19 
                 PmU.fC.mA.mU.mC.mU.mA.mG.mC.mA.mC.mC.mA.fG.mG.mU.mA.mG.mA.mC.mC.fU.fG.fG.mU.mG.mC. 
               
               
                   
                 mU.mA.mG.mA.mU.mG.mA 
               
               
                   
               
               
                  20 
                 PmU.fU.mU.mC.mC.mA.mU.mA.mU.mC.mC.mU.mU.fG.mA.mC.mU.mU.mU.mU.mC.fA.fA.fG.mG.mA.mU. 
               
               
                   
                 mA.mU.mG.mG.mA.mA.mA 
               
               
                   
               
               
                  21 
                 PmU.fG.mA.mU.mC.mC.mA.mU.mC.mU.mA.mG.mC.fA.mC.mC.mA.mG.mG.mG.mU.fG.fC.fU.mA.mG.mA. 
               
               
                   
                 mU.mG.mG.mA.mU.mC.mA 
               
               
                   
               
               
                  22 
                 PmU.fC.mC.mA.mC.mA.mG.mA.mG.mA.mC.mU.mC.fA.mG.mA.mG.mA.mC.mC.mU.fG.fA.fG.mU.mC.mU. 
               
               
                   
                 mC.mU.mG.mU.mG.mG.mA 
               
               
                   
               
               
                  23 
                 PmU.fU.mG.mA.mU.mC.mC.mA.mU.mC.mU.mA.mG.fC.mA.mC.mC.mA.mG.mU.mG.fC.fU.fA.mG.mA.mU. 
               
               
                   
                 mG.mG.mA.mU.mC.mA.mA 
               
               
                   
               
               
                  24 
                 PmU.fA.mC.mC.mU.mC.mC.mU.mU.mC.mC.mG.mA.fG.mU.mC.mA.mG.mC.mA.mC.fU.fC.fG.mG.mA.mA. 
               
               
                   
                 mG.mG.mA.mG.mG.mU.mA 
               
               
                   
               
               
                  25 
                 PmU.fU.mC.mU.mG.mA.mU.mC.mC.mA.mU.mC.mU.fA.mG.mC.mA.mC.mC.mC.mU.fA.fG.fA.mU.mG.mG. 
               
               
                   
                 mA.mU.mC.mA.mG.mA.mA 
               
               
                   
               
               
                  26 
                 PmU.fU.mC.mU.mU.mG.mG.mC.mA.mG.mG.mA.mA.fG.mG.mC.mU.mC.mC.mC.mC.fU.fU.fC.mC.mU.mG. 
               
               
                   
                 mC.mC.mA.mA.mG.mA.mA 
               
               
                   
               
               
                  27 
                 PmU.fU.mC.mU.mA.mG.mC.mA.mC.mC.mA.mG.mG.fU.mA.mG.mA.mU.mG.mU.mA.fC.fC.fU.mG.mG.mU. 
               
               
                   
                 mG.mC.mU.mA.mG.mA.mA 
               
               
                   
               
               
                  28 
                 PmU.fA.mA.mG.mU.mA.mC.mU.mC.mA.mG.mA.mC.fA.mC.mC.mA.mC.mA.mG.mU.fG.fU.fC.mU.mG.mA. 
               
               
                   
                 mG.mU.mA.mC.mU.mU.mA 
               
               
                   
               
               
                  29 
                 PmU.fU.mG.mU.mC.mU.mG.mA.mU.mC.mC.mA.mU.fC.mU.mA.mG.mC.mA.mA.mG.fA.fU.fG.mG.mA.mU. 
               
               
                   
                 mC.mA.mG.mA.mC.mA.mA 
               
               
                   
               
               
                  30 
                 PmU.fA.mU.mC.mU.mA.mG.mC.mA.mC.mC.mA.mG.fG.mU.mA.mG.mA.mU.mA.mC.fC.fU.fG.mG.mU.mG. 
               
               
                   
                 mC.mU.mA.mG.mA.mU.mA 
               
               
                   
               
               
                  31 
                 PmU.fC.mA.mA.mA.mU.mC.mC.mU.mC.mA.mU.mC.fU.mU.mG.mG.mA.mG.mA.mA.fG.fA.fU.mG.mA.mG. 
               
               
                   
                 mG.mA.mU.mU.mU.mG.mA 
               
               
                   
               
               
                  32 
                 PmU.fA.mU.mA.mG.mU.mC.mA.mU.mA.mA.mA.mA.fU.mU.mC.mA.mG.mG.mA.mA.fU.fU.fU.mU.mA.mU. 
               
               
                   
                 mG.mA.mC.mU.mA.mU.mA 
               
               
                   
               
               
                  33 
                 PmU.fA.mG.mG.mA.mU.mG.mA.mU.mG.mA.mC.mA.fU.mG.mG.mC.mG.mG.mC.mA.fU.fG.fU.mC.mA.mU. 
               
               
                   
                 mC.mA.mU.mC.mC.mU.mA 
               
               
                   
               
               
                  34 
                 PmU.fC.mA.mA.mU.mC.mU.mG.mU.mG.mU.mU.mC.fU.mG.mG.mC.mA.mC.mC.mA.fG.fA.fA.mC.mA.mC. 
               
               
                   
                 mA.mG.mA.mU.mU.mG.mA 
               
               
                   
               
               
                  35 
                 PmU.fU.mG.mA.mG.mC.mU.mU.mG.mA.mU.mC.mA.fG.mG.mG.mC.mA.mA.mC.mC.fU.fG.fA.mU.mC.mA. 
               
               
                   
                 mA.mG.mC.mU.mC.mA.mA 
               
               
                   
               
               
                  36 
                 PmU.fA.mG.mU.mG.mG.mA.mA.mA.mG.mA.mG.mA.fU.mC.mU.mC.mA.mU.mG.mA.fU.fC.fU.mC.mU.mU. 
               
               
                   
                 mU.mC.mC.mA.mC.mU.mA 
               
               
                   
               
               
                  37 
                 PmU.fA.mG.mA.mU.mG.mU.mU.mC.mA.mU.mG.mG.fA.mG.mC.mC.mU.mG.mC.mU.fC.fC.fA.mU.mG.mA. 
               
               
                   
                 mA.mC.mA.mU.mC.mU.mA 
               
               
                   
               
               
                  38 
                 PmU.fG.mC.mA.mA.mG.mU.mG.mG.mU.mA.mG.mU.fU.mG.mG.mA.mG.mG.mC.mA.fA.fC.fU.mA.mC.mC. 
               
               
                   
                 mA.mC.mU.mU.mG.mC.mA 
               
               
                   
               
               
                  39 
                 PmU.fC.mA.mC.mA.mC.mC.mA.mU.mA.mA.mC.mU.fU.mG.mC.mC.mA.mC.mC.mA.fA.fG.fU.mU.mA.mU. 
               
               
                   
                 mG.mG.mU.mG.mU.mG.mA 
               
               
                   
               
               
                  40 
                 PmU.fA.mA.mA.mG.mA.mG.mA.mU.mC.mU.mC.mA.fU.mC.mA.mC.mU.mC.mG.mA.fU.fG.fA.mG.mA.mU. 
               
               
                   
                 mC.mU.mC.mU.mU.mU.mA 
               
               
                   
               
               
                  41 
                 PmU.fU.mC.mA.mA.mC.mU.mU.mG.mU.mG.mG.mU.fC.mU.mU.mC.mA.mU.mA.mG.fA.fC.fC.mA.mC.mA. 
               
               
                   
                 mA.mG.mU.mU.mG.mA.mA 
               
               
                   
               
               
                  42 
                 PmU.fA.mA.mA.mC.mG.mA.mC.mU.mU.mC.mU.mC.fU.mU.mG.mU.mG.mA.mA.mA.fG.fA.fG.mA.mA.mG. 
               
               
                   
                 mU.mC.mG.mU.mU.mU.mA 
               
               
                   
               
               
                  43 
                 PmU.fG.mU.mA.mU.mG.mU.mG.mG.mC.mA.mU.mA.fU.mG.mU.mC.mA.mC.mC.mA.fU.fA.fU.mG.mC.mC. 
               
               
                   
                 mA.mC.mA.mU.mA.mC.mA 
               
               
                   
               
               
                  44 
                 PmU.fG.mU.mC.mU.mU.mU.mC.mU.mU.mG.mG.mA.fA.mG.mC.mC.mA.mA.mC.mU.fU.fC.fC.mA.mA.mG. 
               
               
                   
                 mA.mA.mA.mG.mA.mC.mA 
               
               
                   
               
               
                  45 
                 PmU.fC.mA.mU.mC.mC.mA.mG.mA.mU.mA.mA.mU.fC.mC.mU.mC.mC.mC.mG.mG.fA.fU.fU.mA.mU.mC. 
               
               
                   
                 mU.mG.mG.mA.mU.mG.mA 
               
               
                   
               
               
                  46 
                 PmU.fU.mU.mG.mA.mC.mU.mU.mU.mG.mU.mC.mA.fU.mA.mG.mC.mC.mU.mU.mA.fU.fG.fA.mC.mA.mA. 
               
               
                   
                 mA.mG.mU.mC.mA.mA.mA 
               
               
                   
               
               
                  47 
                 PmU.fA.mA.mA.mC.mU.mC.mC.mA.mG.mA.mC.mC.fU.mA.mG.mA.mC.mC.mU.mA.fG.fG.fU.mC.mU.mG. 
               
               
                   
                 mG.mA.mG.mU.mU.mU.mA 
               
               
                   
               
               
                  48 
                 PmU.fA.mU.mA.mA.mC.mU.mU.mG.mC.mC.mA.mC.fC.mU.mU.mC.mU.mC.mA.mG.fG.fU.fG.mG.mC.mA. 
               
               
                   
                 mA.mG.mU.mU.mA.mU.mA 
               
               
                   
               
               
                  49 
                 PmU.fC.mA.mU.mA.mG.mU.mC.mA.mU.mA.mA.mA.fA.mU.mU.mC.mA.mG.mA.mU.fU.fU.fU.mA.mU.mG. 
               
               
                   
                 mA.mC.mU.mA.mU.mG.mA 
               
               
                   
               
               
                  50 
                 PmU.fU.mG.mG.mC.mU.mC.mC.mU.mG.mU.mG.mA.fA.mG.mU.mU.mG.mC.mC.mU.fU.fC.fA.mC.mA.mG. 
               
               
                   
                 mG.mA.mG.mC.mC.mA.mA 
               
               
                   
               
               
                  51 
                 PmU.fA.mA.mA.mG.mU.mA.mC.mU.mC.mA.mG.mA.fC.mA.mC.mC.mA.mC.mU.mG.fU.fC.fU.mG.mA.mG. 
               
               
                   
                 mU.mA.mC.mU.mU.mU.mA 
               
               
                   
               
               
                  52 
                 PmU.fG.mC.mU.mC.mA.mU.mU.mG.mU.mC.mU.mU.fU.mC.mU.mU.mG.mG.mG.mA.fA.fA.fG.mA.mC.mA. 
               
               
                   
                 mA.mU.mG.mA.mG.mC.mA 
               
               
                   
               
               
                  53 
                 PmU.fU.mA.mA.mA.mA.mU.mU.mC.mA.mG.mG.mA.fA.mU.mU.mC.mC.mU.mA.mU.fU.fC.fC.mU.mG.mA. 
               
               
                   
                 mA.mU.mU.mU.mU.mA.mA 
               
               
                   
               
               
                  54 
                 PmU.fG.mA.mG.mA.mU.mC.mU.mU.mG.mG.mC.mC.fU.mG.mC.mC.mA.mU.mC.mA.fG.fG.fC.mC.mA.mA. 
               
               
                   
                 mG.mA.mU.mC.mU.mC.mA 
               
               
                   
               
               
                  55 
                 PmU.fG.mA.mG.mC.mA.mU.mC.mU.mC.mU.mC.mU.fC.mA.mC.mA.mG.mC.mU.mG.fA.fG.fA.mG.mA.mG. 
               
               
                   
                 mA.mU.mG.mC.mU.mC.mA 
               
               
                   
               
               
                  56 
                 PmU.fA.mA.mC.mC.mG.mU.mC.mA.mU.mA.mG.mC.fA.mG.mU.mG.mG.mA.mC.mU.fG.fC.fU.mA.mU.mG. 
               
               
                   
                 mA.mC.mG.mG.mU.mU.mA 
               
               
                   
               
               
                  57 
                 PmU.fA.mG.mA.mG.mC.mU.mU.mU.mG.mA.mU.mA.fU.mC.mC.mU.mG.mU.mG.mA.fU.fA.fU.mC.mA.mA. 
               
               
                   
                 mA.mG.mC.mU.mC.mU.mA 
               
               
                   
               
               
                  58 
                 PmU.fA.mC.mA.mA.mU.mG.mU.mG.mC.mU.mG.mC.fU.mG.mU.mC.mA.mG.mC.mA.fG.fC.fA.mG.mC.mA. 
               
               
                   
                 mC.mA.mU.mU.mG.mU.mA 
               
               
                   
               
               
                  59 
                 PmU.fG.mG.mU.mA.mC.mG.mG.mG.mU.mA.mG.mA.fA.mG.mC.mC.mA.mG.mC.mU.fU.fC.fU.mA.mC.mC. 
               
               
                   
                 mC.mG.mU.mA.mC.mC.mA 
               
               
                   
               
               
                  60 
                 PmU.fC.mA.mG.mA.mC.mC.mU.mA.mG.mA.mC.mC.fU.mG.mG.mU.mC.mA.mC.mA.fG.fG.fU.mC.mU.mA. 
               
               
                   
                 mG.mG.mU.mC.mU.mG.mA 
               
               
                   
               
               
                  61 
                 PmU.fU.mU.mC.mU.mC.mU.mU.mG.mU.mG.mA.mA.fC.mU.mA.mU.mC.mA.mA.mG.fU.fU.fC.mA.mC.mA. 
               
               
                   
                 mA.mG.mA.mG.mA.mA.mA 
               
               
                   
               
               
                  62 
                 PmU.fU.mU.mC.mA.mG.mG.mA.mA.mU.mU.mC.mC.fU.mG.mC.mU.mU.mC.mC.mA.fG.fG.fA.mA.mU.mU. 
               
               
                   
                 mC.mC.mU.mG.mA.mA.mA 
               
               
                   
               
               
                  63 
                 PmU.fC.mC.mA.mG.mG.mU.mU.mU.mU.mC.mC.mA.fU.mA.mU.mC.mC.mU.mU.mA.fU.fG.fG.mA.mA.mA. 
               
               
                   
                 mA.mC.mC.mU.mG.mG.mA 
               
               
                   
               
               
                  64 
                 PmU.fC.mA.mA.mC.mU.mU.mG.mA.mA.mU.mG.mA.fA.mA.mC.mG.mA.mC.mU.mU.fU.fC.fA.mU.mU.mC. 
               
               
                   
                 mA.mA.mG.mU.mU.mG.mA 
               
               
                   
               
               
                  65 
                 PmU.fG.mU.mG.mC.mU.mG.mC.mU.mG.mU.mC.mA.fG.mC.mA.mC.mA.mA.mG.mC.fU.fG.fA.mC.mA.mG. 
               
               
                   
                 mC.mA.mG.mC.mA.mC.mA 
               
               
                   
               
               
                  66 
                 PmU.fG.mA.mC.mC.mU.mC.mC.mU.mU.mC.mC.mG.fA.mG.mU.mC.mA.mG.mC.mU.fC.fG.fG.mA.mA.mG. 
               
               
                   
                 mG.mA.mG.mG.mU.mC.mA 
               
               
                   
               
               
                  67 
                 PmU.fC.mA.mA.mU.mU.mA.mA.mG.mU.mU.mG.mA.fC.mU.mA.mG.mA.mC.mA.mG.fU.fC.fA.mA.mC.mU. 
               
               
                   
                 mU.mA.mA.mU.mU.mG.mA 
               
               
                   
               
               
                  68 
                 PmU.fU.mG.mA.mC.mA.mC.mG.mU.mU.mC.mG.mC.fC.mG.mC.mU.mG.mG.mC.mG.fG.fC.fG.mA.mA.mC. 
               
               
                   
                 mG.mU.mG.mU.mC.mA.mA 
               
               
                   
               
               
                  69 
                 PmU.fC.mA.mU.mU.mG.mU.mC.mU.mU.mU.mC.mU.fU.mG.mG.mA.mA.mG.mC.mA.fA.fG.fA.mA.mA.mG. 
               
               
                   
                 mA.mC.mA.mA.mU.mG.mA 
               
               
                   
               
               
                  70 
                 PmU.fC.mC.mA.mA.mC.mU.mU.mG.mA.mA.mU.mG.fA.mA.mA.mC.mG.mA.mU.mU.fC.fA.fU.mU.mC.mA. 
               
               
                   
                 mA.mG.mU.mU.mG.mG.mA 
               
               
                   
               
               
                  71 
                 PmU.fC.mA.mC.mA.mA.mA.mG.mU.mA.mC.mU.mC.fA.mG.mA.mC.mA.mC.mC.mU.fG.fA.fG.mU.mA.mC. 
               
               
                   
                 mU.mU.mU.mG.mU.mG.mA 
               
               
                   
               
               
                  72 
                 PmU.fU.mG.mC.mA.mG.mU.mG.mG.mU.mA.mG.mG.fU.mG.mA.mC.mG.mC.mC.mA.fC.fC.fU.mA.mC.mC. 
               
               
                   
                 mA.mC.mU.mG.mC.mA.mA 
               
               
                   
               
               
                  73 
                 PmU.fU.mC.mA.mU.mG.mA.mG.mG.mA.mU.mG.mA.fU.mG.mA.mC.mA.mU.mC.mA.fU.fC.fA.mU.mC.mC. 
               
               
                   
                 mU.mC.mA.mU.mG.mA.mA 
               
               
                   
               
               
                  74 
                 PmU.fU.mU.mC.mA.mA.mC.mU.mU.mG.mU.mG.mG.fU.mC.mU.mU.mC.mA.mG.mA.fC.fC.fA.mC.mA.mA. 
               
               
                   
                 mG.mU.mU.mG.mA.mA.mA 
               
               
                   
               
               
                  75 
                 PmU.fG.mU.mA.mG.mU.mU.mG.mG.mA.mG.mG.mA.fA.mG.mC.mC.mU.mC.mC.mU.fU.fC.fC.mU.mC.mC. 
               
               
                   
                 mA.mA.mC.mU.mA.mC.mA 
               
               
                   
               
               
                  76 
                 PmU.fC.mA.mU.mG.mC.mU.mG.mU.mA.mC.mA.mC.fU.mG.mC.mC.mU.mG.mC.mA.fG.fU.fG.mU.mA.mC. 
               
               
                   
                 mA.mG.mC.mA.mU.mG.mA 
               
               
                   
               
               
                  77 
                 PmU.fU.mG.mU.mC.mU.mU.mU.mC.mU.mU.mG.mG.fA.mA.mG.mC.mC.mA.mU.mU.fC.fC.fA.mA.mG.mA. 
               
               
                   
                 mA.mA.mG.mA.mC.mA.mA 
               
               
                   
               
               
                  78 
                 PmU.fC.mG.mA.mC.mU.mC.mC.mU.mU.mC.mU.mA.fU.mG.mG.mU.mC.mU.mC.mA.fU.fA.fG.mA.mA.mG. 
               
               
                   
                 mG.mA.mG.mU.mC.mG.mA 
               
               
                   
               
               
                  79 
                 PmU.fG.mA.mC.mA.mU.mC.mC.mA.mG.mA.mU.mA.fA.mU.mC.mC.mU.mC.mA.mU.fU.fA.fU.mC.mU.mG. 
               
               
                   
                 mG.mA.mU.mG.mU.mC.mA 
               
               
                   
               
               
                  80 
                 PmU.fU.mG.mA.mG.mA.mU.mC.mU.mU.mG.mG.mC.fC.mU.mG.mC.mC.mA.mA.mG.fG.fC.fC.mA.mA.mG. 
               
               
                   
                 mA.mU.mC.mU.mC.mA.mA 
               
               
                   
               
               
                  81 
                 PmU.fA.mC.mG.mC.mU.mG.mU.mC.mU.mU.mC.mA.fA.mG.mG.mC.mG.mG.mC.mU.fU.fG.fA.mA.mG.mA. 
               
               
                   
                 mC.mA.mG.mC.mG.mU.mA 
               
               
                   
               
               
                  82 
                 PmU.fA.mG.mA.mC.mA.mG.mG.mA.mA.mA.mG.mC.fU.mU.mC.mG.mG.mC.mA.mA.fG.fC.fU.mU.mU.mC. 
               
               
                   
                 mC.mU.mG.mU.mC.mU.mA 
               
               
                   
               
               
                  83 
                 PmU.fU.mU.mG.mA.mA.mC.mA.mC.mA.mU.mG.mU.fU.mG.mC.mU.mC.mA.mC.mA.fA.fC.fA.mU.mG.mU. 
               
               
                   
                 mG.mU.mU.mC.mA.mA.mA 
               
               
                   
               
               
                  84 
                 PmU.fA.mU.mA.mA.mA.mA.mU.mU.mC.mA.mG.mG.fA.mA.mU.mU.mC.mC.mU.mU.fC.fC.fU.mG.mA.mA. 
               
               
                   
                 mU.mU.mU.mU.mA.mU.mA 
               
               
                   
               
               
                  85 
                 PmU.fC.mC.mC.mA.mA.mA.mU.mC.mC.mU.mC.mA.fU.mC.mU.mU.mG.mG.mG.mA.fU.fG.fA.mG.mG.mA. 
               
               
                   
                 mU.mU.mU.mG.mG.mG.mA 
               
               
                   
               
               
                  86 
                 PmU.fA.mA.mG.mA.mG.mA.mU.mC.mU.mC.mA.mU.fC.mA.mC.mU.mC.mA.mU.mG.fA.fU.fG.mA.mG.mA. 
               
               
                   
                 mU.mC.mU.mC.mU.mU.mA 
               
               
                   
               
               
                  87 
                 PmU.fA.mA.mA.mG.mC.mA.mU.mU.mG.mA.mU.mG.fU.mU.mC.mA.mC.mU.mA.mA.fC.fA.fU.mC.mA.mA. 
               
               
                   
                 mU.mG.mC.mU.mU.mU.mA 
               
               
                   
               
               
                  88 
                 PmU.fA.mG.mG.mA.mA.mU.mU.mC.mC.mU.mG.mC.fU.mU.mC.mU.mU.mU.mA.mA.fG.fC.fA.mG.mG.mA. 
               
               
                   
                 mA.mU.mU.mC.mC.mU.mA 
               
               
                   
               
               
                  89 
                 PmU.fA.mU.mG.mA.mA.mG.mG.mA.mG.mU.mC.mU.fU.mG.mG.mC.mA.mG.mC.mA.fA.fG.fA.mC.mU.mC. 
               
               
                   
                 mC.mU.mU.mC.mA.mU.mA 
               
               
                   
               
               
                  90 
                 PmU.fA.mA.mG.mC.mU.mU.mC.mG.mG.mC.mC.mA.fC.mC.mU.mC.mU.mU.mG.mG.fU.fG.fG.mC.mC.mG. 
               
               
                   
                 mA.mA.mG.mC.mU.mU.mA 
               
               
                   
               
               
                  91 
                 PmU.fU.mG.mA.mC.mU.mU.mU.mG.mU.mC.mA.mU.fA.mG.mC.mC.mU.mG.mC.mU.fA.fU.fG.mA.mC.mA. 
               
               
                   
                 mA.mA.mG.mU.mC.mA.mA 
               
               
                   
               
               
                  92 
                 PmU.fU.mC.mC.mA.mA.mG.mC.mU.mG.mA.mA.mA.fC.mU.mC.mC.mA.mG.mA.mG.fU.fU.fU.mC.mA.mG. 
               
               
                   
                 mC.mU.mU.mG.mG.mA.mA 
               
               
                   
               
               
                  93 
                 PmU.fC.mC.mA.mA.mA.mU.mC.mC.mU.mC.mA.mU.fC.mU.mU.mG.mG.mA.mA.mG.fA.fU.fG.mA.mG.mG. 
               
               
                   
                 mA.mU.mU.mU.mG.mG.mA 
               
               
                   
               
               
                  94 
                 PmU.fC.mA.mG.mC.mU.mG.mU.mU.mU.mU.mA.mA.fU.mU.mC.mA.mA.mU.mA.mA.fU.fU.fA.mA.mA.mA. 
               
               
                   
                 mC.mA.mG.mC.mU.mG.mA 
               
               
                   
               
               
                  95 
                 PmU.fA.mA.mC.mG.mA.mC.mU.mU.mC.mU.mC.mU.fU.mG.mU.mG.mA.mA.mC.mA.fA.fG.fA.mG.mA.mA. 
               
               
                   
                 mG.mU.mC.mG.mU.mU.mA 
               
               
                   
               
               
                  96 
                 PmU.fC.mC.mG.mG.mA.mA.mC.mA.mU.mC.mC.mA.fA.mG.mC.mG.mG.mG.mC.mU.fU.fG.fG.mA.mU.mG. 
               
               
                   
                 mU.mU.mC.mC.mG.mG.mA 
               
               
                   
               
               
                  97 
                 PmU.fC.mA.mA.mA.mC.mA.mC.mA.mU.mA.mG.mA.fC.mA.mU.mC.mC.mA.mU.mG.fU.fC.fU.mA.mU.mG. 
               
               
                   
                 mU.mG.mU.mU.mU.mG.mA 
               
               
                   
               
               
                  98 
                 PmU.fU.mU.mC.mA.mC.mA.mC.mC.mA.mU.mA.mA.fC.mU.mU.mG.mC.mC.mA.mG.fU.fU.fA.mU.mG.mG. 
               
               
                   
                 mU.mG.mU.mG.mA.mA.mA 
               
               
                   
               
               
                  99 
                 PmU.fU.mC.mU.mC.mU.mU.mG.mU.mG.mA.mA.mC.fU.mA.mU.mC.mA.mA.mU.mA.fG.fU.fU.mC.mA.mC. 
               
               
                   
                 mA.mA.mG.mA.mG.mA.mA 
               
               
                   
               
               
                 100 
                 PmU.fA.mU.mU.mC.mA.mG.mG.mA.mA.mU.mU.mC.fC.mU.mG.mC.mU.mU.mA.mG.fG.fA.fA.mU.mU.mC. 
               
               
                   
                 mC.mU.mG.mA.mA.mU.mA 
               
               
                   
               
               
                 101 
                 PmU.fG.mA.mC.mA.mC.mU.mU.mU.mG.mA.mC.mC.fC.mA.mA.mA.mU.mU.mU.mG.fG.fG.fU.mC.mA.mA. 
               
               
                   
                 mA.mG.mU.mG.mU.mC.mA 
               
               
                   
               
               
                 102 
                 PmU.fC.mA.mC.mA.mA.mA.mC.mA.mG.mA.mG.mC.fU.mU.mU.mG.mA.mU.mA.mA.fG.fC.fU.mC.mU.mG. 
               
               
                   
                 mU.mU.mU.mG.mU.mG.mA 
               
               
                   
               
               
                 103 
                 PmU.fC.mA.mA.mA.mC.mA.mG.mA.mG.mC.mU.mU.fU.mG.mA.mU.mA.mU.mC.mA.fA.fA.fG.mC.mU.mC. 
               
               
                   
                 mU.mG.mU.mU.mU.mG.mA 
               
               
                   
               
               
                 104 
                 PmU.fU.mU.mG.mG.mA.mG.mU.mU.mU.mC.mU.mC.fC.mU.mU.mC.mA.mG.mA.mG.fG.fA.fG.mA.mA.mA. 
               
               
                   
                 mC.mU.mC.mC.mA.mA.mA 
               
               
                   
               
               
                 105 
                 PmU.fU.mC.mA.mC.mA.mC.mC.mA.mU.mA.mA.mC.fU.mU.mG.mC.mC.mA.mA.mA.fG.fU.fU.mA.mU.mG. 
               
               
                   
                 mG.mU.mG.mU.mG.mA.mA 
               
               
                   
               
               
                 106 
                 PmU.fU.mG.mA.mA.mU.mG.mA.mA.mA.mC.mG.mA.fC.mU.mU.mC.mU.mC.mA.mG.fU.fC.fG.mU.mU.mU. 
               
               
                   
                 mC.mA.mU.mU.mC.mA.mA 
               
               
                   
               
               
                 107 
                 PmU.fC.mA.mG.mG.mU.mU.mU.mU.mC.mC.mA.mU.fA.mU.mC.mC.mU.mU.mA.mU.fA.fU.fG.mG.mA.mA. 
               
               
                   
                 mA.mA.mC.mC.mU.mG.mA 
               
               
                   
               
               
                 108 
                 PmU.fG.mC.mA.mU.mC.mU.mC.mU.mC.mU.mC.mA.fC.mA.mG.mC.mU.mG.mU.mG.fU.fG.fA.mG.mA.mG. 
               
               
                   
                 mA.mG.mA.mU.mG.mC.mA 
               
               
                   
               
               
                 109 
                 PmU.fA.mC.mA.mU.mC.mC.mA.mG.mA.mU.mA.mA.fU.mC.mC.mU.mC.mC.mG.mA.fU.fU.fA.mU.mC.mU. 
               
               
                   
                 mG.mG.mA.mU.mG.mU.mA 
               
               
                   
               
               
                 110 
                 PmU.fC.mG.mA.mG.mU.mU.mG.mU.mU.mC.mC.mC.fU.mC.mG.mG.mU.mG.mG.mA.fG.fG.fG.mA.mA.mC. 
               
               
                   
                 mA.mA.mC.mU.mC.mG.mA 
               
               
                   
               
               
                 111 
                 PmU.fA.mC.mA.mC.mA.mU.mG.mU.mU.mG.mC.mU.fC.mA.mU.mU.mG.mU.mU.mG.fA.fG.fC.mA.mA.mC. 
               
               
                   
                 mA.mU.mG.mU.mG.mU.mA 
               
               
                   
               
               
                 112 
                 PmU.fU.mC.mU.mC.mA.mA.mU.mU.mA.mA.mG.mU.fU.mG.mA.mC.mU.mA.mC.mA.fA.fC.fU.mU.mA.mA. 
               
               
                   
                 mU.mU.mG.mA.mG.mA.mA 
               
               
                   
               
               
                 113 
                 PmU.fG.mA.mA.mG.mC.mC.mA.mA.mA.mG.mC.mA.fU.mU.mG.mA.mU.mG.mA.mA.fU.fG.fC.mU.mU.mU. 
               
               
                   
                 mG.mG.mC.mU.mU.mC.mA 
               
               
                   
               
               
                 114 
                 PmU.fG.mC.mA.mG.mU.mG.mG.mA.mA.mA.mG.mA.fG.mA.mU.mC.mU.mC.mU.mC.fU.fC.fU.mU.mU.mC. 
               
               
                   
                 mC.mA.mC.mU.mG.mC.mA 
               
               
                   
               
               
                 115 
                 PmU.fA.mC.mA.mC.mU.mG.mC.mC.mU.mG.mG.mA.fG.mG.mG.mC.mC.mU.mC.mC.fU.fC.fC.mA.mG.mG. 
               
               
                   
                 mC.mA.mG.mU.mG.mU.mA 
               
               
                   
               
               
                 116 
                 PmU.fU.mA.mG.mA.mC.mC.mU.mG.mG.mU.mC.mA.fC.mA.mU.mU.mC.mC.mU.mG.fU.fG.fA.mC.mC.mA. 
               
               
                   
                 mG.mG.mU.mC.mU.mA.mA 
               
               
                   
               
               
                 117 
                 PmU.fC.mA.mG.mA.mC.mA.mC.mA.mA.mA.mC.mA.fG.mA.mG.mC.mU.mU.mU.mC.fU.fG.fU.mU.mU.mG. 
               
               
                   
                 mU.mG.mU.mC.mU.mG.mA 
               
               
                   
               
               
                 118 
                 PmU.fG.mA.mG.mU.mU.mU.mC.mU.mC.mC.mU.mU.fC.mA.mG.mC.mC.mA.mU.mG.fA.fA.fG.mG.mA.mG. 
               
               
                   
                 mA.mA.mA.mC.mU.mC.mA 
               
               
                   
               
               
                 119 
                 PmU.fA.mU.mG.mU.mG.mC.mU.mG.mC.mU.mG.mU.fC.mA.mG.mC.mA.mC.mU.mG.fA.fC.fA.mG.mC.mA. 
               
               
                   
                 mG.mC.mA.mC.mA.mU.mA 
               
               
                   
               
               
                 120 
                 PmU.fC.mA.mG.mA.mG.mC.mU.mU.mU.mG.mA.mU.fA.mU.mC.mC.mU.mG.mA.mU.fA.fU.fC.mA.mA.mA. 
               
               
                   
                 mG.mC.mU.mC.mU.mG.mA 
               
               
                   
               
               
                 121 
                 PmU.fG.mA.mU.mA.mU.mC.mC.mU.mG.mU.mG.mC.fA.mG.mG.mG.mA.mG.mC.mU.fG.fC.fA.mC.mA.mG. 
               
               
                   
                 mG.mA.mU.mA.mU.mC.mA 
               
               
                   
               
               
                 122 
                 PmU.fA.mG.mG.mG.mC.mA.mA.mC.mG.mU.mC.mA.fU.mA.mG.mU.mC.mA.mU.mA.fU.fG.fA.mC.mG.mU. 
               
               
                   
                 mU.mG.mC.mC.mC.mU.mA 
               
               
                   
               
               
                 123 
                 PmU.fA.mG.mA.mC.mC.mU.mA.mG.mA.mC.mC.mU.fG.mG.mU.mC.mA.mC.mC.mC.fA.fG.fG.mU.mC.mU. 
               
               
                   
                 mA.mG.mG.mU.mC.mU.mA 
               
               
                   
               
               
                 124 
                 PmU.fA.mG.mU.mA.mC.mU.mC.mA.mG.mA.mC.mA.fC.mC.mA.mC.mA.mG.mG.mG.fU.fG.fU.mC.mU.mG. 
               
               
                   
                 mA.mG.mU.mA.mC.mU.mA 
               
               
                   
               
               
                 125 
                 PmU.fA.mA.mG.mG.mC.mU.mC.mC.mG.mU.mC.mC.fC.mG.mC.mU.mC.mC.mC.mG.fG.fG.fA.mC.mG.mG. 
               
               
                   
                 mA.mG.mC.mC.mU.mU.mA 
               
               
                   
               
               
                 126 
                 PmU.fG.mG.mG.mC.mA.mA.mC.mG.mU.mC.mA.mU.fA.mG.mU.mC.mA.mU.mC.mU.fA.fU.fG.mA.mC.mG. 
               
               
                   
                 mU.mU.mG.mC.mC.mC.mA 
               
               
                   
               
               
                 127 
                 PmU.fC.mU.mG.mU.mU.mU.mU.mA.mA.mU.mU.mC.fA.mA.mU.mC.mC.mC.mU.mU.fG.fA.fA.mU.mU.mA. 
               
               
                   
                 mA.mA.mA.mC.mA.mG.mA 
               
               
                   
               
               
                 128 
                 PmU.fA.mG.mA.mG.mA.mU.mC.mU.mC.mA.mU.mC.fA.mC.mU.mC.mA.mC.mG.mU.fG.fA.fU.mG.mA.mG. 
               
               
                   
                 mA.mU.mC.mU.mC.mU.mA 
               
               
                   
               
               
                 129 
                 PmU.fG.mG.mU.mC.mU.mU.mC.mA.mU.mA.mA.mU.fU.mG.mA.mU.mU.mU.mC.mA.fA.fU.fU.mA.mU.mG. 
               
               
                   
                 mA.mA.mG.mA.mC.mC.mA 
               
               
                   
               
               
                 130 
                 PmU.fC.mA.mU.mA.mU.mC.mU.mU.mG.mG.mC.mU.fU.mC.mA.mC.mA.mC.mG.mA.fA.fG.fC.mC.mA.mA. 
               
               
                   
                 mG.mA.mU.mA.mU.mG.mA 
               
               
                   
               
               
                 131 
                 PmU.fC.mA.mC.mC.mA.mA.mC.mU.mU.mG.mA.mA.fU.mG.mA.mA.mA.mC.mC.mA.fU.fU.fC.mA.mA.mG. 
               
               
                   
                 mU.mU.mG.mG.mU.mG.mA 
               
               
                   
               
               
                 132 
                 PmU.fA.mG.mC.mU.mG.mU.mU.mU.mU.mA.mA.mU.fU.mC.mA.mA.mU.mC.mG.mA.fA.fU.fU.mA.mA.mA. 
               
               
                   
                 mA.mC.mA.mG.mC.mU.mA 
               
               
                   
               
               
                 133 
                 PmU.fU.mA.mA.mC.mU.mU.mG.mC.mC.mA.mC.mC.fU.mU.mC.mU.mC.mA.mA.mA.fG.fG.fU.mG.mG.mC. 
               
               
                   
                 mA.mA.mG.mU.mU.mA.mA 
               
               
                   
               
               
                 134 
                 PmU.fU.mG.mA.mG.mC.mA.mG.mG.mU.mA.mC.mC.fU.mG.mC.mU.mU.mU.mC.mA.fG.fG.fU.mA.mC.mC. 
               
               
                   
                 mU.mG.mC.mU.mC.mA.mA 
               
               
                   
               
               
                 135 
                 PmU.fU.mU.mG.mA.mU.mG.mU.mA.mG.mA.mC.mC.fU.mC.mC.mU.mU.mC.mG.mA.fG.fG.fU.mC.mU.mA. 
               
               
                   
                 mC.mA.mU.mC.mA.mA.mA 
               
               
                   
               
               
                 136 
                 PmU.fG.mG.mC.mA.mA.mG.mU.mG.mG.mU.mA.mG.fU.mU.mG.mG.mA.mG.mA.mA.fC.fU.fA.mC.mC.mA. 
               
               
                   
                 mC.mU.mU.mG.mC.mC.mA 
               
               
                   
               
               
                 137 
                 PmU.fG.mG.mA.mA.mG.mC.mC.mU.mC.mA.mA.mA.fG.mC.mU.mC.mG.mA.mG.mC.fU.fU.fU.mG.mA.mG. 
               
               
                   
                 mG.mC.mU.mU.mC.mC.mA 
               
               
                   
               
               
                 138 
                 PmU.fA.mA.mU.mG.mA.mC.mA.mG.mU.mA.mA.mU.fU.mG.mG.mG.mU.mC.mC.mA.fA.fU.fU.mA.mC.mU. 
               
               
                   
                 mG.mU.mC.mA.mU.mU.mA 
               
               
                   
               
               
                 139 
                 PmU.fU.mU.mU.mG.mA.mA.mC.mA.mC.mA.mU.mG.fU.mU.mG.mC.mU.mC.mA.mA.fC.fA.fU.mG.mU.mG. 
               
               
                   
                 mU.mU.mC.mA.mA.mA.mA 
               
               
                   
               
               
                 140 
                 PmU.fA.mA.mA.mU.mC.mC.mU.mC.mA.mU.mC.mU.fU.mG.mG.mA.mG.mU.mC.mA.fA.fG.fA.mU.mG.mA. 
               
               
                   
                 mG.mG.mA.mU.mU.mU.mA 
               
               
                   
               
               
                 141 
                 PmU.fG.mG.mA.mG.mU.mU.mU.mC.mU.mC.mC.mU.fU.mC.mA.mG.mC.mC.mG.mA.fA.fG.fG.mA.mG.mA. 
               
               
                   
                 mA.mA.mC.mU.mC.mC.mA 
               
               
                   
               
               
                 142 
                 PmU.fC.mA.mU.mA.mA.mC.mU.mU.mG.mC.mC.mA.fC.mC.mU.mU.mC.mU.mG.mG.fU.fG.fG.mC.mA.mA. 
               
               
                   
                 mG.mU.mU.mA.mU.mG.mA 
               
               
                   
               
               
                 143 
                 PmU.fG.mC.mU.mG.mU.mU.mU.mU.mA.mA.mU.mU.fC.mA.mA.mU.mC.mC.mU.mG.fA.fA.fU.mU.mA.mA. 
               
               
                   
                 mA.mA.mC.mA.mG.mC.mA 
               
               
                   
               
               
                 144 
                 PmU.fA.mA.mG.mC.mU.mC.mG.mA.mG.mU.mU.mG.fU.mU.mC.mC.mC.mU.mA.mA.fC.fA.fA.mC.mU.mC. 
               
               
                   
                 mG.mA.mG.mC.mU.mU.mA 
               
               
                   
               
               
                 145 
                 PmU.fG.mG.mC.mA.mA.mC.mG.mU.mC.mA.mU.mA.fG.mU.mC.mA.mU.mA.mA.mC.fU.fA.fU.mG.mA.mC. 
               
               
                   
                 mG.mU.mU.mG.mC.mC.mA 
               
               
                   
               
               
                 146 
                 PmU.fU.mU.mC.mC.mA.mG.mG.mU.mU.mU.mU.mC.fC.mA.mU.mA.mU.mC.mU.mG.fG.fA.fA.mA.mA.mC. 
               
               
                   
                 mC.mU.mG.mG.mA.mA.mA 
               
               
                   
               
               
                 147 
                 PmU.fU.mC.mC.mA.mG.mG.mU.mU.mU.mU.mC.mC.fA.mU.mA.mU.mC.mC.mA.mU.fG.fG.fA.mA.mA.mA. 
               
               
                   
                 mC.mC.mU.mG.mG.mA.mA 
               
               
                   
               
               
                 148 
                 PmU.fC.mC.mA.mU.mG.mU.mU.mG.mU.mG.mC.mA.fA.mU.mC.mC.mA.mU.mA.mU.fU.fG.fC.mA.mC.mA. 
               
               
                   
                 mA.mC.mA.mU.mG.mG.mA 
               
               
                   
               
               
                 149 
                 PmU.fC.mA.mU.mA.mU.mC.mC.mU.mU.mG.mA.mC.fU.mU.mU.mG.mA.mA.mA.mA.fG.fU.fC.mA.mA.mG. 
               
               
                   
                 mG.mA.mU.mA.mU.mG.mA 
               
               
                   
               
               
                 150 
                 PmU.fU.mG.mA.mC.mU.mU.mU.mG.mA.mA.mC.mA.fC.mA.mU.mG.mU.mU.mU.mG.fU.fG.fU.mU.mC.mA. 
               
               
                   
                 mA.mA.mG.mU.mC.mA.mA 
               
               
                   
               
               
                 151 
                 PmU.fC.mU.mC.mA.mU.mC.mU.mU.mG.mG.mA.mG.fU.mU.mU.mC.mU.mC.mA.mA.fC.fU.fC.mC.mA.mA. 
               
               
                   
                 mG.mA.mU.mG.mA.mG.mA 
               
               
                   
               
               
                 152 
                 PmU.fC.mA.mU.mG.mU.mU.mG.mC.mU.mC.mA.mU.fU.mG.mU.mC.mU.mU.mC.mA.fA.fU.fG.mA.mG.mC. 
               
               
                   
                 mA.mA.mC.mA.mU.mG.mA 
               
               
                   
               
               
                 153 
                 PmU.fA.mC.mC.mA.mA.mC.mU.mU.mG.mA.mA.mU.fG.mA.mA.mA.mC.mG.mU.mC.fA.fU.fU.mC.mA.mA. 
               
               
                   
                 mG.mU.mU.mG.mG.mU.mA 
               
               
                   
               
               
                 154 
                 PmU.fA.mC.mA.mG.mA.mU.mC.mG.mC.mU.mG.mU.fC.mU.mG.mC.mC.mC.mA.mG.fA.fC.fA.mG.mC.mG. 
               
               
                   
                 mA.mU.mC.mU.mG.mU.mA 
               
               
                   
               
               
                 155 
                 PmU.fU.mC.mA.mC.mA.mG.mC.mU.mG.mC.mC.mU.fU.mU.mC.mU.mU.mA.mA.mA.fA.fG.fG.mC.mA.mG. 
               
               
                   
                 mC.mU.mG.mU.mG.mA.mA 
               
               
                   
               
               
                 156 
                 PmU.fG.mG.mC.mC.mG.mC.mC.mA.mG.mA.mA.mU.fC.mA.mC.mC.mU.mC.mU.mG.fA.fU.fU.mC.mU.mG. 
               
               
                   
                 mG.mC.mG.mG.mC.mC.mA 
               
               
                   
               
               
                 157 
                 PmU.fC.mC.mA.mA.mG.mC.mU.mG.mA.mA.mA.mC.fU.mC.mC.mA.mG.mA.mG.mA.fG.fU.fU.mU.mC.mA. 
               
               
                   
                 mG.mC.mU.mU.mG.mG.mA 
               
               
                   
               
               
                 158 
                 PmU.fU.mU.mG.mA.mU.mC.mA.mG.mG.mG.mC.mA.fA.mC.mG.mU.mC.mA.mG.mU.fU.fG.fC.mC.mC.mU. 
               
               
                   
                 mG.mA.mU.mC.mA.mA.mA 
               
               
                   
               
               
                 159 
                 PmU.fG.mU.mU.mC.mC.mC.mA.mA.mA.mC.mC.mA.fU.mG.mC.mC.mA.mC.mC.mA.fU.fG.fG.mU.mU.mU. 
               
               
                   
                 mG.mG.mG.mA.mA.mC.mA 
               
               
                   
               
               
                 160 
                 PmU.fA.mC.mC.mU.mG.mC.mU.mU.mU.mU.mG.mC.fC.mG.mC.mU.mU.mC.mC.mG.fG.fC.fA.mA.mA.mA. 
               
               
                   
                 mG.mC.mA.mG.mG.mU.mA 
               
               
                   
               
               
                 161 
                 PmU.fU.mU.mG.mC.mU.mC.mA.mU.mU.mG.mU.mC.fU.mU.mU.mC.mU.mU.mA.mA.fG.fA.fC.mA.mA.mU. 
               
               
                   
                 mG.mA.mG.mC.mA.mA.mA 
               
               
                   
               
               
                 162 
                 PmU.fC.mA.mC.mG.mU.mU.mC.mG.mC.mC.mG.mC.fU.mG.mG.mG.mA.mG.mC.mA.fG.fC.fG.mG.mC.mG. 
               
               
                   
                 mA.mA.mC.mG.mU.mG.mA 
               
               
                   
               
               
                 163 
                 PmU.fC.mA.mU.mU.mC.mU.mU.mG.mA.mU.mG.mU.fA.mG.mA.mC.mC.mU.mC.mU.fA.fC.fA.mU.mC.mA. 
               
               
                   
                 mA.mG.mA.mA.mU.mG.mA 
               
               
                   
               
               
                 164 
                 PmU.fU.mU.mG.mA.mG.mC.mU.mU.mG.mA.mU.mC.fA.mG.mG.mG.mC.mA.mC.mU.fG.fA.fU.mC.mA.mA. 
               
               
                   
                 mG.mC.mU.mC.mA.mA.mA 
               
               
                   
               
               
                 165 
                 PmU.fA.mU.mU.mC.mU.mU.mG.mA.mU.mG.mU.mA.fG.mA.mC.mC.mU.mC.mU.mC.fU.fA.fC.mA.mU.mC. 
               
               
                   
                 mA.mA.mG.mA.mA.mU.mA 
               
               
                   
               
               
                 166 
                 PmU.fU.mG.mA.mA.mG.mG.mA.mG.mU.mC.mU.mU.fG.mG.mC.mA.mG.mG.mC.mC.fA.fA.fG.mA.mC.mU. 
               
               
                   
                 mC.mC.mU.mU.mC.mA.mA 
               
               
                   
               
               
                 167 
                 PmU.fU.mU.mG.mG.mC.mU.mU.mC.mA.mC.mA.mC.fC.mA.mU.mA.mA.mC.mU.mG.fG.fU.fG.mU.mG.mA. 
               
               
                   
                 mA.mG.mC.mC.mA.mA.mA 
               
               
                   
               
               
                 168 
                 PmU.fA.mU.mC.mU.mU.mG.mG.mC.mU.mU.mC.mA.fC.mA.mC.mC.mA.mU.mU.mG.fU.fG.fA.mA.mG.mC. 
               
               
                   
                 mC.mA.mA.mG.mA.mU.mA 
               
               
                   
               
               
                 169 
                 PmU.fC.mU.mC.mA.mC.mA.mG.mC.mU.mG.mC.mC.fU.mU.mU.mC.mU.mU.mA.mA.fG.fG.fC.mA.mG.mC. 
               
               
                   
                 mU.mG.mU.mG.mA.mG.mA 
               
               
                   
               
               
                 170 
                 PmU.fC.mC.mA.mA.mU.mG.mC.mU.mG.mU.mC.mU.fG.mA.mU.mC.mC.mA.mU.mC.fA.fG.fA.mC.mA.mG. 
               
               
                   
                 mC.mA.mU.mU.mG.mG.mA 
               
               
                   
               
               
                 171 
                 PmU.fG.mA.mG.mU.mG.mG.mU.mG.mG.mU.mC.mA.fC.mA.mC.mC.mU.mC.mU.mG.fU.fG.fA.mC.mC.mA. 
               
               
                   
                 mC.mC.mA.mC.mU.mC.mA 
               
               
                   
               
               
                 172 
                 PmU.fA.mU.mA.mG.mG.mG.mA.mC.mU.mC.mA.mC.fU.mC.mC.mU.mC.mC.mG.mA.fG.fU.fG.mA.mG.mU. 
               
               
                   
                 mC.mC.mC.mU.mA.mU.mA 
               
               
                   
               
               
                 173 
                 PmU.fC.mU.mG.mA.mC.mU.mU.mC.mA.mA.mC.mU.fU.mG.mU.mG.mG.mU.mC.mA.fA.fG.fU.mU.mG.mA. 
               
               
                   
                 mA.mG.mU.mC.mA.mG.mA 
               
               
                   
               
               
                 174 
                 PmU.fU.mU.mC.mU.mC.mA.mA.mU.mU.mA.mA.mG.fU.mU.mG.mA.mC.mU.mA.mA.fC.fU.fU.mA.mA.mU. 
               
               
                   
                 mU.mG.mA.mG.mA.mA.mA 
               
               
                   
               
               
                 175 
                 PmU.fA.mG.mU.mU.mU.mC.mU.mC.mC.mU.mU.mC.fA.mG.mC.mC.mA.mG.mC.mU.fG.fA.fA.mG.mG.mA. 
               
               
                   
                 mG.mA.mA.mA.mC.mU.mA 
               
               
                   
               
               
                 176 
                 PmU.fA.mG.mC.mU.mU.mU.mG.mA.mU.mA.mU.mC.fC.mU.mG.mU.mG.mC.mA.mG.fG.fA.fU.mA.mU.mC. 
               
               
                   
                 mA.mA.mA.mG.mC.mU.mA 
               
               
                   
               
               
                 177 
                 PmU.fU.mG.mU.mC.mC.mU.mU.mG.mA.mC.mU.mU.fU.mG.mU.mC.mA.mU.mC.mA.fA.fA.fG.mU.mC.mA. 
               
               
                   
                 mA.mG.mG.mA.mC.mA.mA 
               
               
                   
               
               
                 178 
                 PmU.fC.mA.mG.mG.mU.mA.mC.mG.mU.mG.mU.mC.fU.mG.mC.mA.mC.mA.mC.mA.fG.fA.fC.mA.mC.mG. 
               
               
                   
                 mU.mA.mC.mC.mU.mG.mA 
               
               
                   
               
               
                 179 
                 PmU.fA.mA.mA.mC.mA.mA.mU.mG.mU.mG.mC.mU.fG.mC.mU.mG.mU.mC.mG.mC.fA.fG.fC.mA.mC.mA. 
               
               
                   
                 mU.mU.mG.mU.mU.mU.mA 
               
               
                   
               
               
                 180 
                 PmU.fA.mU.mA.mU.mC.mC.mU.mG.mU.mG.mC.mA.fG.mG.mG.mA.mG.mC.mC.mC.fU.fG.fC.mA.mC.mA. 
               
               
                   
                 mG.mG.mA.mU.mA.mU.mA 
               
               
                   
               
               
                 181 
                 PmU.fG.mA.mC.mU.mC.mA.mG.mA.mG.mA.mC.mU.fG.mG.mC.mU.mU.mU.mC.mC.fA.fG.fU.mC.mU.mC. 
               
               
                   
                 mU.mG.mA.mG.mU.mC.mA 
               
               
                   
               
               
                 182 
                 PmU.fC.mA.mA.mU.mG.mA.mC.mA.mG.mU.mA.mA.fU.mU.mG.mG.mG.mU.mA.mA.fU.fU.fA.mC.mU.mG. 
               
               
                   
                 mU.mC.mA.mU.mU.mG.mA 
               
               
                   
               
               
                 183 
                 PmU.fG.mA.mG.mC.mC.mA.mC.mC.mU.mU.mC.mC.fU.mG.mA.mC.mA.mC.mC.mA.fG.fG.fA.mA.mG.mG. 
               
               
                   
                 mU.mG.mG.mC.mU.mC.mA 
               
               
                   
               
               
                 184 
                 PmU.fC.mU.mU.mG.mA.mC.mU.mU.mU.mG.mA.mA.fC.mA.mC.mA.mU.mG.mU.mG.fU.fU.fC.mA.mA.mA. 
               
               
                   
                 mG.mU.mC.mA.mA.mG.mA 
               
               
                   
               
               
                 185 
                 PmU.fA.mU.mG.mA.mA.mA.mC.mG.mA.mC.mU.mU.fC.mU.mC.mU.mU.mG.mA.mG.fA.fA.fG.mU.mC.mG. 
               
               
                   
                 mU.mU.mU.mC.mA.mU.mA 
               
               
                   
               
               
                 186 
                 PmU.fG.mA.mA.mG.mA.mC.mA.mG.mG.mA.mA.mA.fG.mC.mU.mU.mC.mG.mG.mC.fU.fU.fU.mC.mC.mU. 
               
               
                   
                 mG.mU.mC.mU.mU.mC.mA 
               
               
                   
               
               
                 187 
                 PmU.fG.mC.mU.mU.mU.mG.mA.mU.mA.mU.mC.mC.fU.mG.mU.mG.mC.mA.mC.mA.fG.fG.fA.mU.mA.mU. 
               
               
                   
                 mC.mA.mA.mA.mG.mC.mA 
               
               
                   
               
               
                 188 
                 PmU.fU.mC.mU.mU.mG.mA.mG.mC.mU.mU.mG.mA.fU.mC.mA.mG.mG.mG.mG.mA.fU.fC.fA.mA.mG.mC. 
               
               
                   
                 mU.mC.mA.mA.mG.mA.mA 
               
               
                   
               
               
                 189 
                 PmU.fG.mG.mA.mU.mU.mG.mC.mU.mC.mU.mG.mC.fA.mC.mU.mC.mU.mG.mG.mU.fG.fC.fA.mG.mA.mG. 
               
               
                   
                 mC.mA.mA.mU.mC.mC.mA 
               
               
                   
               
               
                 190 
                 PmU.fC.mA.mU.mA.mU.mU.mG.mA.mG.mC.mA.mU.fC.mU.mC.mU.mC.mU.mA.mG.fA.fU.fG.mC.mU.mC. 
               
               
                   
                 mA.mA.mU.mA.mU.mG.mA 
               
               
                   
               
               
                 191 
                 PmU.fA.mU.mC.mC.mU.mU.mG.mA.mC.mU.mU.mU.fG.mA.mA.mC.mA.mC.mU.mC.fA.fA.fA.mG.mU.mC. 
               
               
                   
                 mA.mA.mG.mG.mA.mU.mA 
               
               
                   
               
               
                 192 
                 PmU.fG.mC.mA.mG.mA.mC.mA.mU.mC.mC.mA.mC.fU.mA.mC.mU.mC.mC.mU.mA.fG.fU.fG.mG.mA.mU. 
               
               
                   
                 mG.mU.mC.mU.mG.mC.mA 
               
               
                   
               
               
                 193 
                 PmU.fA.mG.mA.mC.mC.mU.mC.mC.mU.mU.mC.mC.fG.mA.mG.mU.mC.mA.mU.mC.fG.fG.fA.mA.mG.mG. 
               
               
                   
                 mA.mG.mG.mU.mC.mU.mA 
               
               
                   
               
               
                 194 
                 PmU.fA.mC.mC.mU.mU.mC.mU.mC.mA.mA.mU.mU.fA.mA.mG.mU.mU.mG.mU.mU.fA.fA.fU.mU.mG.mA. 
               
               
                   
                 mG.mA.mA.mG.mG.mU.mA 
               
               
                   
               
               
                 195 
                 PmU.fA.mG.mA.mA.mG.mU.mC.mG.mG.mA.mA.mG.fG.mA.mG.mC.mC.mG.mU.mC.fC.fU.fU.mC.mC.mG. 
               
               
                   
                 mA.mC.mU.mU.mC.mU.mA 
               
               
                   
               
               
                 196 
                 PmU.fU.mG.mC.mA.mC.mA.mG.mG.mG.mU.mA.mC.fG.mG.mG.mU.mA.mG.mC.mC.fG.fU.fA.mC.mC.mC. 
               
               
                   
                 mU.mG.mU.mG.mC.mA.mA 
               
               
                   
               
               
                 197 
                 PmU.fA.mU.mG.mA.mC.mA.mG.mU.mA.mA.mU.mU.fG.mG.mG.mU.mC.mC.mC.mC.fA.fA.fU.mU.mA.mC. 
               
               
                   
                 mU.mG.mU.mC.mA.mU.mA 
               
               
                   
               
               
                 198 
                 PmU.fG.mU.mU.mA.mG.mU.mC.mC.mC.mU.mG.mA.fC.mU.mU.mC.mA.mA.mA.mG.fU.fC.fA.mG.mG.mG. 
               
               
                   
                 mA.mC.mU.mA.mA.mC.mA 
               
               
                   
               
               
                 199 
                 PmU.fA.mU.mA.mU.mC.mC.mU.mU.mG.mA.mC.mU.fU.mU.mG.mA.mA.mC.mA.mA.fA.fG.fU.mC.mA.mA. 
               
               
                   
                 mG.mG.mA.mU.mA.mU.mA 
               
               
                   
               
               
                 200 
                 PmU.fG.mU.mA.mC.mG.mU.mG.mU.mC.mU.mG.mC.fA.mC.mA.mG.mG.mG.mG.mU.fG.fC.fA.mG.mA.mC. 
               
               
                   
                 mA.mC.mG.mU.mA.mC.mA 
               
               
                   
               
               
                 201 
                 PmU.fG.mU.mC.mA.mG.mC.mA.mC.mA.mA.mA.mG.fU.mA.mC.mU.mC.mA.mU.mA.fC.fU.fU.mU.mG.mU. 
               
               
                   
                 mG.mC.mU.mG.mA.mC.mA 
               
               
                   
               
               
                 202 
                 PmU.fU.mG.mG.mU.mC.mU.mU.mC.mA.mU.mA.mA.fU.mU.mG.mA.mU.mU.mA.mA.fU.fU.fA.mU.mG.mA. 
               
               
                   
                 mA.mG.mA.mC.mC.mA.mA 
               
               
                   
               
               
                 203 
                 PmU.fC.mA.mG.mA.mG.mA.mC.mU.mC.mA.mG.mA.fG.mA.mC.mU.mG.mG.mU.mC.fU.fC.fU.mG.mA.mG. 
               
               
                   
                 mU.mC.mU.mC.mU.mG.mA 
               
               
                   
               
               
                 204 
                 PmU.fU.mA.mG.mA.mC.mA.mU.mC.mC.mA.mG.mA.fU.mA.mA.mU.mC.mC.mU.mA.fU.fC.fU.mG.mG.mA. 
               
               
                   
                 mU.mG.mU.mC.mU.mA.mA 
               
               
                   
               
               
                 205 
                 PmU.fC.mU.mC.mC.mU.mU.mC.mC.mG.mA.mG.mU.fC.mA.mG.mC.mU.mU.mU.mG.fA.fC.fU.mC.mG.mG. 
               
               
                   
                 mA.mA.mG.mG.mA.mG.mA 
               
               
                   
               
               
                 206 
                 PmU.fC.mA.mU.mG.mG.mA.mG.mC.mC.mU.mG.mA.fA.mG.mG.mG.mU.mC.mC.mU.fU.fC.fA.mG.mG.mC. 
               
               
                   
                 mU.mC.mC.mA.mU.mG.mA 
               
               
                   
               
               
                 207 
                 PmU.fU.mG.mG.mC.mA.mU.mA.mU.mG.mU.mC.mA.fC.mU.mA.mG.mA.mC.mA.mG.fU.fG.fA.mC.mA.mU. 
               
               
                   
                 mA.mU.mG.mC.mC.mA.mA 
               
               
                   
               
               
                 208 
                 PmU.fA.mA.mG.mC.mA.mU.mU.mG.mA.mU.mG.mU.fU.mC.mA.mC.mU.mU.mG.mA.fA.fC.fA.mU.mC.mA. 
               
               
                   
                 mA.mU.mG.mC.mU.mU.mA 
               
               
                   
               
               
                 209 
                 PmU.fC.mU.mC.mA.mC.mU.mC.mC.mU.mC.mC.mA.fG.mU.mA.mC.mA.mA.mA.mC.fU.fG.fG.mA.mG.mG. 
               
               
                   
                 mA.mG.mU.mG.mA.mG.mA 
               
               
                   
               
               
                 210 
                 PmU.fG.mA.mU.mG.mU.mC.mC.mU.mU.mG.mA.mC.fU.mU.mU.mG.mU.mC.mA.mA.fG.fU.fC.mA.mA.mG. 
               
               
                   
                 mG.mA.mC.mA.mU.mC.mA 
               
               
                   
               
               
                 211 
                 PmU.fU.mG.mU.mU.mU.mU.mA.mA.mU.mU.mC.mA.fA.mU.mC.mC.mC.mA.mA.mU.fU.fG.fA.mA.mU.mU. 
               
               
                   
                 mA.mA.mA.mA.mC.mA.mA 
               
               
                   
               
               
                 212 
                 PmU.fU.mA.mG.mA.mU.mG.mU.mU.mC.mA.mU.mG.fG.mA.mG.mC.mC.mU.mU.mC.fC.fA.fU.mG.mA.mA. 
               
               
                   
                 mC.mA.mU.mC.mU.mA.mA 
               
               
                   
               
               
                 213 
                 PmU.fA.mU.mA.mG.mC.mA.mG.mU.mG.mG.mA.mA.fA.mG.mA.mG.mA.mU.mC.mU.fU.fU.fC.mC.mA.mC. 
               
               
                   
                 mU.mG.mC.mU.mA.mU.mA 
               
               
                   
               
               
                 214 
                 PmU.fC.mA.mU.mU.mC.mA.mC.mU.mU.mG.mG.mC.fA.mG.mG.mU.mG.mC.mC.mU.fG.fC.fC.mA.mA.mG. 
               
               
                   
                 mU.mG.mA.mA.mU.mG.mA 
               
               
                   
               
               
                 215 
                 PmU.fA.mU.mU.mG.mA.mU.mG.mU.mU.mC.mA.mC.fU.mU.mG.mG.mU.mU.mA.mA.fG.fU.fG.mA.mA.mC. 
               
               
                   
                 mA.mU.mC.mA.mA.mU.mA 
               
               
                   
               
               
                 216 
                 PmU.fC.mA.mG.mC.mC.mA.mG.mG.mG.mC.mA.mG.fC.mA.mC.mU.mU.mG.mU.mG.fC.fU.fG.mC.mC.mC. 
               
               
                   
                 mU.mG.mG.mC.mU.mG.mA 
               
               
                   
               
               
                 217 
                 PmU.fC.mU.mC.mA.mG.mU.mG.mU.mC.mC.mA.mA.fG.mC.mU.mG.mA.mA.mG.mC.fU.fU.fG.mG.mA.mC. 
               
               
                   
                 mA.mC.mU.mG.mA.mG.mA 
               
               
                   
               
               
                 218 
                 PmU.fC.mA.mG.mA.mG.mA.mC.mU.mG.mG.mC.mU.fU.mU.mC.mA.mU.mC.mA.mA.fA.fG.fC.mC.mA.mG. 
               
               
                   
                 mU.mC.mU.mC.mU.mG.mA 
               
               
                   
               
               
                 219 
                 PmU.fA.mU.mC.mC.mA.mG.mA.mU.mA.mA.mU.mC.fC.mU.mC.mC.mC.mU.mA.mG.fG.fA.fU.mU.mA.mU. 
               
               
                   
                 mC.mU.mG.mG.mA.mU.mA 
               
               
                   
               
               
                 220 
                 PmU.fC.mU.mU.mC.mU.mC.mA.mA.mU.mU.mA.mA.fG.mU.mU.mG.mA.mC.mA.mC.fU.fU.fA.mA.mU.mU. 
               
               
                   
                 mG.mA.mG.mA.mA.mG.mA 
               
               
                   
               
               
                 221 
                 PmU.fC.mC.mA.mG.mA.mC.mC.mU.mA.mG.mA.mC.fC.mU.mG.mG.mU.mC.mA.mG.fG.fU.fC.mU.mA.mG. 
               
               
                   
                 mG.mU.mC.mU.mG.mG.mA 
               
               
                   
               
               
                 222 
                 PmU.fC.mA.mA.mC.mG.mU.mC.mA.mU.mA.mG.mU.fC.mA.mU.mA.mA.mA.mU.mG.fA.fC.fU.mA.mU.mG. 
               
               
                   
                 mA.mC.mG.mU.mU.mG.mA 
               
               
                   
               
               
                 223 
                 PmU.fU.mU.mG.mA.mA.mU.mG.mA.mA.mA.mC.mG.fA.mC.mU.mU.mC.mU.mG.mU.fC.fG.fU.mU.mU.mC. 
               
               
                   
                 mA.mU.mU.mC.mA.mA.mA 
               
               
                   
               
               
                 224 
                 PmU.fC.mC.mU.mC.mC.mU.mC.mA.mG.mA.mC.mA.fC.mA.mA.mA.mC.mA.mU.mG.fU.fG.fU.mC.mU.mG. 
               
               
                   
                 mA.mG.mG.mA.mG.mG.mA 
               
               
                   
               
               
                 225 
                 PmU.fA.mA.mG.mC.mC.mA.mA.mA.mG.mC.mA.mU.fU.mG.mA.mU.mG.mU.mC.mA.fA.fU.fG.mC.mU.mU. 
               
               
                   
                 mU.mG.mG.mC.mU.mU.mA 
               
               
                   
               
               
                 226 
                 PmU.fU.mG.mA.mA.mA.mC.mG.mA.mC.mU.mU.mC.fU.mC.mU.mU.mG.mU.mG.mA.fG.fA.fA.mG.mU.mC. 
               
               
                   
                 mG.mU.mU.mU.mC.mA.mA 
               
               
                   
               
               
                 227 
                 PmU.fA.mA.mC.mU.mU.mG.mU.mG.mG.mU.mC.mU.fU.mC.mA.mU.mA.mA.mG.mA.fA.fG.fA.mC.mC.mA. 
               
               
                   
                 mC.mA.mA.mG.mU.mU.mA 
               
               
                   
               
               
                 228 
                 PmU.fC.mC.mA.mG.mG.mU.mA.mG.mA.mU.mG.mU.fU.mC.mA.mU.mG.mG.mG.mA.fA.fC.fA.mU.mC.mU. 
               
               
                   
                 mA.mC.mC.mU.mG.mG.mA 
               
               
                   
               
               
                 229 
                 PmU.fC.mU.mG.mU.mG.mU.mU.mC.mU.mG.mG.mC.fA.mC.mC.mU.mG.mC.mG.mU.fG.fC.fC.mA.mG.mA. 
               
               
                   
                 mA.mC.mA.mC.mA.mG.mA 
               
               
                   
               
               
                 230 
                 PmU.fA.mA.mC.mU.mU.mG.mC.mC.mA.mC.mC.mU.fU.mC.mU.mC.mA.mA.mG.mA.fA.fG.fG.mU.mG.mG. 
               
               
                   
                 mC.mA.mA.mG.mU.mU.mA 
               
               
                   
               
               
                 231 
                 PmU.fG.mC.mC.mA.mU.mG.mG.mU.mU.mG.mC.mU.fU.mG.mU.mG.mG.mU.mC.mA.fA.fG.fC.mA.mA.mC. 
               
               
                   
                 mC.mA.mU.mG.mG.mC.mA 
               
               
                   
               
               
                 232 
                 PmU.fG.mA.mC.mA.mA.mA.mU.mG.mG.mG.mC.mC.fU.mG.mA.mU.mA.mG.mC.mA.fG.fG.fC.mC.mC.mA. 
               
               
                   
                 mU.mU.mU.mG.mU.mC.mA 
               
               
                   
               
               
                 233 
                 PmU.fA.mA.mG.mU.mU.mG.mA.mC.mU.mA.mG.mA.fC.mA.mC.mU.mU.mU.mU.mG.fU.fC.fU.mA.mG.mU. 
               
               
                   
                 mC.mA.mA.mC.mU.mU.mA 
               
               
                   
               
               
                 234 
                 PmU.fC.mA.mU.mG.mG.mC.mG.mG.mG.mU.mG.mC.fG.mG.mU.mU.mC.mC.mC.mC.fG.fC.fA.mC.mC.mC. 
               
               
                   
                 mG.mC.mC.mA.mU.mG.mA 
               
               
                   
               
               
                 235 
                 PmU.fC.mC.mG.mG.mA.mU.mC.mU.mC.mA.mU.mC.fA.mA.mU.mG.mA.mC.mU.mU.fG.fA.fU.mG.mA.mG. 
               
               
                   
                 mA.mU.mC.mC.mG.mG.mA 
               
               
                   
               
               
                 236 
                 PmU.fG.mA.mG.mG.mA.mA.mG.mC.mC.mU.mC.mA.fA.mA.mG.mC.mU.mC.mU.mU.fU.fG.fA.mG.mG.mC. 
               
               
                   
                 mU.mU.mC.mC.mU.mC.mA 
               
               
                   
               
               
                 237 
                 PmU.fA.mC.mU.mU.mU.mG.mA.mA.mC.mA.mC.mA.fU.mG.mU.mU.mG.mC.mC.mA.fU.fG.fU.mG.mU.mU. 
               
               
                   
                 mC.mA.mA.mA.mG.mU.mA 
               
               
                   
               
               
                 238 
                 PmU.fC.mU.mC.mC.mU.mC.mC.mU.mC.mA.mG.mA.fC.mA.mC.mA.mA.mA.mU.mG.fU.fC.fU.mG.mA.mG. 
               
               
                   
                 mG.mA.mG.mG.mA.mG.mA 
               
               
                   
               
               
                 239 
                 PmU.fA.mG.mG.mA.mA.mG.mG.mC.mU.mC.mC.mG.fU.mC.mC.mC.mG.mC.mG.mA.fC.fG.fG.mA.mG.mC. 
               
               
                   
                 mC.mU.mU.mC.mC.mU.mA 
               
               
                   
               
               
                 240 
                 PmU.fC.mG.mC.mC.mA.mG.mA.mA.mU.mC.mA.mC.fC.mU.mC.mU.mG.mC.mA.mG.fG.fU.fG.mA.mU.mU. 
               
               
                   
                 mC.mU.mG.mG.mC.mG.mA 
               
               
                   
               
               
                 241 
                 PmU.fG.mG.mA.mA.mA.mG.mA.mG.mA.mU.mC.mU.fC.mA.mU.mC.mA.mC.mU.mG.fA.fG.fA.mU.mC.mU. 
               
               
                   
                 mC.mU.mU.mU.mC.mC.mA 
               
               
                   
               
               
                 242 
                 PmU.fA.mA.mG.mU.mC.mC.mC.mG.mG.mA.mU.mC.fU.mC.mA.mU.mC.mA.mG.mA.fG.fA.fU.mC.mC.mG. 
               
               
                   
                 mG.mG.mA.mC.mU.mU.mA 
               
               
                   
               
               
                 243 
                 PmU.fG.mA.mG.mC.mU.mU.mG.mA.mU.mC.mA.mG.fG.mG.mC.mA.mA.mC.mC.mC.fC.fU.fG.mA.mU.mC. 
               
               
                   
                 mA.mA.mG.mC.mU.mC.mA 
               
               
                   
               
               
                 244 
                 PmU.fG.mU.mU.mG.mC.mU.mC.mA.mU.mU.mG.mU.fC.mU.mU.mU.mC.mU.mA.mG.fA.fC.fA.mA.mU.mG. 
               
               
                   
                 mA.mG.mC.mA.mA.mC.mA 
               
               
                   
               
               
                 245 
                 PmU.fU.mG.mC.mU.mU.mG.mU.mG.mG.mU.mA.mA.fU.mC.mG.mG.mU.mA.mG.mA.fU.fU.fA.mC.mC.mA. 
               
               
                   
                 mC.mA.mA.mG.mC.mA.mA 
               
               
                   
               
               
                 246 
                 PmU.fU.mC.mA.mU.mC.mA.mC.mU.mC.mA.mC.mA.fU.mU.mG.mU.mA.mG.mA.mA.fU.fG.fU.mG.mA.mG. 
               
               
                   
                 mU.mG.mA.mU.mG.mA.mA 
               
               
                   
               
               
                 247 
                 PmU.fC.mA.mG.mU.mG.mU.mC.mC.mA.mA.mG.mC.fU.mG.mA.mA.mA.mC.mC.mA.fG.fC.fU.mU.mG.mG. 
               
               
                   
                 mA.mC.mA.mC.mU.mG.mA 
               
               
                   
               
               
                 248 
                 PmU.fC.mC.mA.mU.mU.mC.mU.mU.mG.mA.mU.mG.fU.mA.mG.mA.mC.mC.mU.mA.fC.fA.fU.mC.mA.mA. 
               
               
                   
                 mG.mA.mA.mU.mG.mG.mA 
               
               
                   
               
               
                 249 
                 PmU.fA.mA.mC.mA.mA.mU.mG.mU.mG.mC.mU.mG.fC.mU.mG.mU.mC.mA.mA.mG.fC.fA.fG.mC.mA.mC. 
               
               
                   
                 mA.mU.mU.mG.mU.mU.mA 
               
               
                   
               
               
                 250 
                 PmU.fG.mA.mC.mU.mU.mC.mA.mA.mC.mU.mU.mG.fU.mG.mG.mU.mC.mU.mC.mA.fC.fA.fA.mG.mU.mU. 
               
               
                   
                 mG.mA.mA.mG.mU.mC.mA 
               
               
                   
               
               
                 106- 
                 mU.fU.mG.fA.mA.fU.mG.fA.mA.fA.mC.fG.mA.fC.mU.fU.mC.fU.mC.fG.mU.fU.mU.fC.mA.fU.mU. 
               
               
                 13(4) 
                 fC.mA.fA.3xGalNAc 
               
               
                 as + 
                   
               
               
                 s 
                   
               
               
                 13(5) 
                 mU.fU.mG.mC.mC.mA.mC.mA.mG.mA.mG.mA.mC.fU.mC.mA.mG.mA.mG.mA.fG.fU.fC.mU.mC.mU.mG. 
               
               
                 as + 
                 mU.mG.mG.mC.mA.mA.3xGalNAc 
               
               
                 s 
               
               
                   
               
               
                 Note = 
               
               
                 Each of the above constructs may or may not have a phosphate modification at the 5′ end group. Furthermore, and independently, each of the above constructs may or may not have a “3x GalNAc” coupled to the 3′ end group. Advantageously the constructs employ a 3x GalNAc ligand, in particular a toothbrush ligand as defined herein. Particularly advantageous are 
               
               
                 constructs which in addition have a 5′ phosphate, even though this is not a strict requirement, given that in the absence thereof, mammalian cells will add such phosphate in case it is absent from the molecule as administered. 
               
            
           
         
       
     
     Table 4 below shows constructs “106-13(4) as+s” and “13(5) as+s” with their internucleoside linkages. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 modified hairpin constructs including internucleo- 
               
               
                 side linkages 
               
            
           
           
               
               
            
               
                 # 
                   
               
               
                   
               
               
                 13(5) 
                 5′-usUfsgccacagagacUfscsasgsasgsaGfUf 
               
               
                 as + s 
                 Cfucuguggcsasas(SO-GalNAc)(SO-GalNAc) 
               
               
                   
                 (SO-GalNAc)-3′ 
               
               
                   
               
               
                 106-13(4) 
                 5′-usUfsgAfaUfgAfaAfcGfasCfsusUfscsUf 
               
               
                 as + s 
                 scGfuUfuCfaUfuCfsasAfs(SO-GalNAc)(SO- 
               
               
                   
                 GalNAc)(SO-GalNAc)-3′ 
               
               
                   
               
               
                 Notes about the nomenclature in the table: 
               
               
                 Nf: 2′-Fluoro residues 
               
               
                 n: 2′-O-methyl residues 
               
               
                 (invA): inverted ribo-A 
               
               
                 (invG): inverted ribo-G 
               
               
                 s: phosphorothioate 
               
               
                 p: phosphate 
               
               
                 (SO-GaNAc): Simaomics mono-GalNAc building block, also referred to as “toothbrush” herein 
               
            
           
         
       
     
     The sequences corresponding to those in the Tables above, where the 5′ nucleoside of the antisense (guide) strand (first region as defined in the claims herein) can include any nucleobase that can be present in an RNA molecule, in other words can be any of adenine (A), uracil (U), guanine (G) or cytosine (C). Additionally, the 3′ nucleoside of the sense (passenger) strand (second region as defined in the claims herein) can include any nucleobase that can be present in an RNA molecule, in other words can be any of adenine (A), uracil (U), guanine (G) or cytosine (C), advantageously, however, a nucleobase that is complementary to the 5′ nucleobase of the antisense (guide) strand (first region as defined herein). 
     While the methods are shown and described as being a series of acts that are performed in a particular sequence, it is to be understood and appreciated that the methods are not limited by the order of the sequence. For example, some acts can occur in a different order than what is described herein. In addition, an act can occur concurrently with another act. Further, in some instances, not all acts may be required to implement a method described herein. 
     The order of the steps of the methods described herein is exemplary, but the steps may be carried out in any suitable order, or simultaneously where appropriate. Additionally, steps may be added or substituted in, or individual steps may be deleted from any of the methods without departing from the scope of the subject matter described herein. Aspects of any of the Examples described above may be combined with aspects of any of the other Examples described to form further Examples. 
     It will be understood that the above description of a specific embodiment is given by way of example only and that various modifications may be made by those skilled in the art. What has been described above includes Examples of one or more embodiments. It is, of course, not possible to describe every conceivable modification and alteration of the above compounds, compositions or methods for purposes of describing the aforementioned aspects, but one of ordinary skill in the art can recognize that many further modifications and permutations of various aspects are possible. Accordingly, the described aspects are intended to embrace all such alterations, modifications, and variations that fall within the scope of the appended claims. 
     EXAMPLES 
     The following Examples illustrate certain embodiments of the present disclosure and are not limiting. Moreover, where specific embodiments are provided, the inventors have contemplated generic application of those specific embodiments. For example, disclosure of an oligonucleotide having a particular motif or modification patterns provides reasonable support for additional oligonucleotides having the same or similar motif or modification patterns. 
     The syntheses of the RNAi constructs disclosed herein have been carried out using synthesis methods known to the person skilled in the art, such as synthesis methods disclosed in https://en.wikipedia.org/wiki/Oligonucleotide_synthesis {retrieved on 16 Feb. 2022}, where the methods disclosed on this website are incorporated by reference herein in their entirety. The only difference to the synthesis method disclosed in this reference is that GalNAc phosphoramidite immobilized on a support is used in the synthesis method during the first synthesis step. 
     Example 1: 
     Materials and Methods 
     Cell Culture: 
     HepG2 (ATCC cat. 85011430) cells were maintained by biweekly passing in EMEM supplemented with 10% FBS, 20 mM L-glutamine, 10 mM HEPES pH 7.2, 1 mM sodium pyruvate, 1× MEM non-essential amino acids, and 1× Pen/Strep (EMEM complete). CFB Target identification and duplex preparation: 
     Oligomeric compounds targeting CFB were identified by bioinformatic analysis on human CFB mRNA sequence as given in RefSeq sequence ID NM_001710.5. 250 compounds were selected for synthesis as asymmetric duplexes. Compounds were dissolved to 50 uM in molecular biology grade water and annealed by heating at 95 C for 5 minutes followed by gradual cooling to room temperature. 
     CFB—Primary Screen: 
     On the day of transfection, HepG2 cells were collected by trypsinization, counted, and seeded in 96 well tissue culture treated plates at 10,000 cells per well in 50 uL complete EMEM with 20% FBS. Cells were allowed to rest for 4 hours before transfection with 2 pmoles of each respective CFB-targeting oligomeric compound in triplicate via RNAiMax (ThermoFisher). In brief, 8 pmoles of each compound were diluted in 100 uL OptiMEM and mixed gently with 0.8 uL of RNAiMax in 100 uL OptiMEM to make 200 uL total complex. 50 uL of each RNAiMax complexed compound was added to each respective triplicate well of HepG2 cells for a final mixture of 20 nM compound in a volume of 100 uL, 50/50 EMEM/OptiMEM at 10% FBS. 72 hours post transfection, cells were harvested and RNA isolated using the PureLink Pro 96 total RNA Purification Kit (ThermoFisher, 12173011A) according to the manufacturer protocol. Harvested RNA was assayed for CFB expression via Taqman qPCR using the Luna Universal Probe One-Step RT-qPCR Kit (NEB, E3006). Two separate qPCR assays were performed for each sample using two separate CFB Taqman probe sets multiplexed with a common GAPDH VIC probe (ThermoFisher, 4326317E). Thermocycling and data acquisition was performed with an Applied Biosystems QuantStudio 3 Real-Time PCR System. 
     CFB—Secondary Screen: 
     Based on data from the primary screen, a yet narrower set of the best performing 30 CFB-targeting constructs were tested in dose curves. As before, HepG2 cells were collected by trypsinization and seeded in 96 well tissue culture plates at 10,000 cells per well in 50 uL complete EMEM with 20% FBS and allowed to rest for 4 hours. Transfection complexes were formed by gently mixing 36 pmoles of each compound in 180 uL OptiMEM with 2.16 uL RNAiMax in 180 uL OptiMEM to make 360 uL total complex. A two fold dilution series was then performed with basal OptiMEM. 50 uL of each dilution was added to respective triplicates of HepG2 cells to make a final dilution series of 50 nM down to 0.32 nM in a volume of 100 uL, 50/50 EMEM/OptiMEM at 10% FBS. 
     72 hours post transfection, cells were harvested and RNA isolated using the PureLink Pro 96 total RNA Purification Kit (ThermoFisher, 12173011A) according to the manufacturer protocol. Harvested RNA was assayed for CFB expression via Taqman qPCR using the Luna Universal Probe One-Step RT-qPCR Kit (NEB, E3006). A single qPCR assay was performed for each sample using CFB Taqman probe set multiplexed with a common GAPDH VIC probe (ThermoFisher, 4326317E). Thermocycling and data acquisition was performed with an Applied Biosystems QuantStudio 3 Real-Time PCR System. 
     Example 2 
     Results 
     Table 5 below shows IC50 values (in nM) for 30 specific constructs selected in accordance with the Examples. Max % KD indicates the maximally achieved knock-down with 0% being no knock-down and 100% full knock-down. 
     
       
         
           
               
               
               
               
             
               
                   
                   
               
               
                   
                 CFB Sequence ID 
                 IC50 
                 Max % KD 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
            
               
                   
                 CFB94 
                 4.36 
                 83 
               
               
                   
                 CFB247 
                 4.42 
                 84 
               
               
                   
                 CFB13 
                 5.72 
                 93 
               
               
                   
                 CFB106 
                 5.84 
                 88 
               
               
                   
                 CFB28 
                 6.24 
                 84 
               
               
                   
                 CFB135 
                 6.91 
                 89 
               
               
                   
                 CFB132 
                 6.92 
                 87 
               
               
                   
                 CFB32 
                 6.96 
                 81 
               
               
                   
                 CFB83 
                 7.17 
                 88 
               
               
                   
                 CFB102 
                 7.39 
                 83 
               
               
                   
                 CFB62 
                 7.61 
                 90 
               
               
                   
                 CFB241 
                 7.84 
                 82 
               
               
                   
                 CFB09 
                 8.02 
                 92 
               
               
                   
                 CFB54 
                 8.24 
                 82 
               
               
                   
                 CFB143 
                 8.81 
                 82 
               
               
                   
                 CFB103 
                 9.16 
                 80 
               
               
                   
                 CFB128 
                 9.22 
                 83 
               
               
                   
                 CFB53 
                 9.52 
                 83 
               
               
                   
                 CFB150 
                 10.33 
                 83 
               
               
                   
                 CFB82 
                 10.34 
                 88 
               
               
                   
                 CFB36 
                 10.64 
                 79 
               
               
                   
                 CFB25 
                 10.88 
                 81 
               
               
                   
                 CFB71 
                 11.47 
                 84 
               
               
                   
                 CFB17 
                 11.60 
                 77 
               
               
                   
                 CFB05 
                 12.67 
                 75 
               
               
                   
                 CFB141 
                 13.37 
                 77 
               
               
                   
                 CFB90 
                 13.78 
                 85 
               
               
                   
                 CFB127 
                 14.04 
                 73 
               
               
                   
                 CFB75 
                 16.45 
                 69 
               
               
                   
                 CFB95 
                 19.25 
                 72 
               
               
                   
                   
               
            
           
         
       
     
     The IC50 data in the single- to low double-digit nanomolar range demonstrate outstanding performance of numerous constructs as described herein. 
     Example 3 
     Materials and Methods 
     Cell Culture: 
     Human primary hepatocytes (5 donor pooled—Sekisui XenoTech, HPCH05+) were thawed immediately prior to experimentation and cultured in 1× complete Williams medium (Gibco, A1217601) supplemented with Hepatocytes plating supplement pack (Gibco, CM3000). FBS concentration was modified from manufacture recipe to a final 2.5% (as opposed to 5%) for compound stability. 
     1× Complete WEM: 2.5% FBS, 1 μM Dexamethasone, Pen/Strep (100 U/mL/100 μg/mL), 4 μg/ml Human Insulin, 2 mM GlutaMAX, 15 mM HEPES, pH 7.4. 
     Hepatocytes were plated on Collagen I (rat tail) coated 96 well tissue culture plates (Gibco, A1142803). 
     CFB Compound Preparation: 
     Compounds were dissolved to 200 μM in water and annealed by heating at 95 C for 5 minutes followed by rapid cooling on ice. 
     CFB Compound Transfections: 
     On the day of transfection, primary human hepatocytes were thawed in 45 mL of human OptiThaw (Sekisui XenoTech, K8000) and centrifuged down at 200 g for 5 minutes. Cells were resuspended in 2× complete WEM and counted. Cell were then plated in 50 μL of 2× complete WEM at 25,000 cells per well on 96 well type 1 rat tail Collagen plates and allowed to rest and attach for four hours before transfection. 
     Compounds were diluted further to 2 μM in basal WEM. A seven step, five fold dilution series was prepared in basal WEM from 2 μM to 0.000128 μM. 50 μL of each dilution was added to respective triplicates of the plated hepatocytes for a final dilution series of 1 μM down to 0.000064 μM in a volume of 100 uL 1× complete WEM. 
     72 hours post transfection, cells were harvested and RNA isolated using the PureLink Pro 96 total RNA Purification Kit (ThermoFisher, 12173011A) according to the manufacturer protocol. Harvested RNA was assayed for CFB expression via TaqMan qPCR using the Luna Universal Probe One-Step RT-qPCR Kit (NEB, E3006). A single qPCR assay was performed for each sample using an CFB TaqMan probe set (Hs01011282_g1-FAM) multiplexed with a common GAPDH VIC probe (ThermoFisher, 4326317E). Thermocycling and data acquisition was performed with an Applied Biosystems QuantStudio 3/5 Real-Time PCR System. 
     Results 
     The results of the in vitro studies of this example are shown in  FIG.  1   . 
     Example 4 
     Pharmacodynamics Study of STP144G Following Single/Repeat Subcutaneous Injection to Non-Naïve Cynomolgus Monkeys. 
     Study Protocol 
     The following study protocol has been drafted before the animal experiments and studies have been completed and therefore uses the future tense. However, as the study has already been completely carried out, each usage of “future tense” shall be considered as the “past tense” in the following description of the study protocol. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Study Design 
               
            
           
           
               
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                 TOTAL 
                   
                   
               
               
                   
                   
                   
                 Target 
                 Target Dose 
                 Target Dose 
               
               
                   
                   
                 Test 
                 Dose Level 
                 Volume 
                 Concentration 
                 Dose 
               
               
                 Group 
                 # of Males 
                 Article 
                 (mg/animal) 
                 (mL) 
                 (mg/mL) 
                 Route 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1 
                 4 non-naïve 
                 saline 
                 — 
                 3.0 mL 
                 — 
                 SC 
               
               
                 2 
                 4 non-naïve 
                 STP144G 
                 2.5 (Target 
                 3.0 mL 
                 1 
                 SC 
               
               
                   
                   
                 (106-13(4)) 
                 as 1 mg/kg) 
               
               
                 3 
                 4 non-naïve 
                 STP144G 
                 7.5 (Target 
                 3.0 mL 
                 3 
                 SC 
               
               
                   
                   
                 (106-13(4)) 
                 as 3 mg/kg) 
               
               
                 4 
                 4 non-naïve 
                 STP144G 
                 25 (Target 
                 3.0 mL 
                 10 
                 SC 
               
               
                   
                   
                 (106-13(4)) 
                 as 10 mg/kg) 
               
               
                 5 
                 4 non-naïve 
                 STP144G 
                 7.5 (Target 
                 3.0 mL 
                 3 
                 SC 
               
               
                   
                   
                 (106-13(4)) 
                 as 3 mg/kg) 
               
               
                 6 
                 4 non-naïve 
                 STP144G 
                 2.5 (Target 
                 3.0 mL 
                 1 
                 SC 
               
               
                   
                   
                 (13-5) 
                 as 1 mg/kg) 
               
               
                 7 
                 4 non-naïve 
                 STP144G 
                 7.5 (Target 
                 3.0 mL 
                 3 
                 SC 
               
               
                   
                   
                 (13-5) 
                 as 3 mg/kg) 
               
               
                 8 
                 4 non-naïve 
                 STP144G 
                 25 (Target 
                 3.0 mL 
                 10 
                 SC 
               
               
                   
                   
                 (13-5) 
                 as 10 mg/kg) 
               
               
                 9 
                 4 non-naïve 
                 STP144G 
                 7.5 (Target 
                 3.0 mL 
                 3 
                 SC 
               
               
                   
                   
                 (13-5) 
                 as 3 mg/kg) 
               
               
                   
               
               
                 Note: 
               
               
                 1. Test article storage: at 4° C., protected from light (DO NOT FREEZE the test article) 
               
               
                 2. For all groups, animals will be fed on daily diet. 
               
               
                 3. For all groups, saline will be used for vehicles 
               
            
           
         
       
     
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Dose and Sample Collections 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                   
                 Group 
                 Day −7 
                 Day 0 
                 Wk 1 
                 Wk 2 
                 Wk 3 
                 Wk 4 
                 Wk 5 
                 Wk 6 
                 Wk 7 
                 Wk 8 
                 Wk 9 
                 Wk 10 
                 Wk 11 
                 Wk 12 
                 Wk 13 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Dose 
                 1 
                   
                 QD 
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                   
                 2 
                   
                 QD 
               
               
                   
                 3 
                   
                 QD 
               
               
                   
                 4 
                   
                 QD 
               
               
                   
                 5 
                   
                 QD 
                 QD 
                 QD 
               
               
                   
                 6 
                   
                 QD 
               
               
                   
                 7 
                   
                 QD 
               
               
                   
                 8 
                   
                 QD 
               
               
                   
                 9 
                   
                 QD 
                 QD 
                 QD 
               
               
                 Clinical 
                 1-9 
                 BI, 
                   
                 BI, 
                 BI, 
                 BI, 
                 BI, 
                   
                 BI, 
                   
                 BI, 
                   
                 BI, 
                   
                   
                 BI, 
               
               
                 Pathology  a   
                   
                 Se 
                   
                 Se 
                 Se 
                 Se 
                 Se 
                   
                 Se 
                   
                 Se 
                   
                 Se 
                   
                   
                 Se 
               
               
                 Pharmaco- 
                 1-9 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
                 P, 
               
               
                 dynamics  b   
                   
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
                 Se 
               
               
                   
               
               
                 1. Wk 1 point should be 7 days after Day 0; Wk 2 point should be 14 days after Day 0. 
               
               
                 2. Single dose with single compound, subcutaneous injection. For Day 0, Wk 1, and Wk 2, animals will be dosed after all sample collections. 
               
               
                   a  Blood samples collected for clinical pathology will be 2.0 mL in (K2)EDTA anticoagulant for hematology and 1.4 mL in a plain tube (no anticoagulant) for serum chemistry as indicated in Section 4.1.3. 
               
               
                   b  Blood samples collected for pharmacodynamics will be 2 mL in K2EDTA for Complement Factor B and 2 mL in a plain tube (no anticoagulant) as indicated in Section 4.1.4. 
               
            
           
         
       
     
     1 Study Information 
     1.1 Study Objective 
     The objective of this study is to determine the pharmacodynamics (PD) of STP144G following a single/repeat subcutaneous (SC) administration in male cynomolgus monkeys. 
     1.2 Regulatory Compliance 
     This study will be conducted at WuXi AppTec Co., Ltd., (hereafter WuXi) and in accordance with the WuXi Institutional Animal Care and Use Committee (IACUC) standard animal procedures along with the IACUC guidelines that are in compliance with the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals. 
     This study will be conducted in accordance with this protocol and protocol amendments (if applicable) and the associated study-specific procedures, and with applicable WuXi Standard Operating Procedures (SOPs) and generally recognized good laboratory practices. This study will not be considered within the scope of the Good Laboratory Practice regulations. Test Article and Vehicle Information 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Test Article 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                   
                   
                 Molecular 
                 Molecular 
                   
                   
                   
                   
               
               
                   
                 Lot/Batch 
                 Weight of 
                 Weight of 
                 Salt 
                 Chemical 
                 Purity 
               
               
                 Test Article 
                 Number 
                 Free Base 
                 Salt 
                 Factor 
                 Formula 
                 (%) 
                 Storage 
               
               
                   
               
               
                 STP144G 
                 K1 
                 Refer to 
                 Refer to 
                 Refer to 
                 Refer to 
                 83% 
                 4 C. 
               
               
                 (106-13(4) 
                   
                 product 
                 product 
                 product 
                 product 
               
               
                 as + s) 
                   
                 CoA 
                 CoA 
                 CoA 
                 CoA 
               
               
                 STP144G 
                 K1 
                 Refer to 
                 Refer to 
                 Refer to 
                 Refer to 
                 83% 
                 4 C. 
               
               
                 (13-5 as + 
                   
                 product 
                 product 
                 product 
                 product 
               
               
                 s) 
                   
                 CoA 
                 CoA 
                 CoA 
                 CoA 
               
               
                   
               
               
                 *Free base 
               
               
                 NA = Not applicable 
               
               
                 Storage Conditions: Store at 4 C. (DO NOT FREEZE the test article), protected from light 
               
               
                 Handling Instructions: Standard laboratory precautions as defined in WuXi SOPs 
               
               
                 Dose Preparation: Doses will be prepared according to instructions provided by the sponsor. A copy of the instructions, as well as details of preparation, will be maintained in the study records. 
               
               
                 Disposition of Remaining Test Article Formulations: Remaining formulations will be stored at 4° C. 
               
               
                 Disposition of Remaining Test Article (dry powder or solid): Remaining test article will be shipped back to sponsor or discarded 6 months after the final report is signed or at approval of Sponsor. 
               
            
           
         
       
     
     2.2 Negative Control and Vehicle 
     The vehicles will be prepared at WuXi AppTec Co. Details will be documented in the raw data. 
     2.3 Formulation Preparation 
     Ready-to-inject formulations will be provided by Sirnaomics. 
     Test System Identification 
     3.1 Animal Specifications 
     
       
         
           
               
               
             
               
                   
               
             
            
               
                 Species 
                 Cynomolgus monkeys ( Macaca    fascicularis ) 
               
               
                 Justification for Species 
                 This is an acceptable species to support PD 
               
               
                 Selection 
                 studies for compounds intended to use 
               
               
                   
                 in humans. 
               
               
                 History of Dosing 
                 36 non-naïve animals 
               
               
                 Body Weight Range 
                 2.5 kg in average 
               
               
                 Age 
                 2.0-3.0 years old 
               
               
                 Sex 
                 Male 
               
               
                 Source 
                 Hainan Jingang Laboratory Animal Co. 
               
               
                   
                 Ltd and other permitted vendor 
               
               
                 Address of Supplier 
                 Nayangxintan Fucheng Town, Qiongshan 
               
               
                   
                 District, Haikou Hainan Province, 
               
               
                   
                 P.R. China 
               
               
                 Method of Identification 
                 Unique skin tattoo on chest 
               
               
                 Justification for number of 
                 The number of animals in each group 
               
               
                 Animals 
                 is the minimum number of animals 
               
               
                   
                 necessary for assessment of interanimal 
               
               
                   
                 variability. 
               
               
                 Selection of Animals 
                 45 males will be selected 
               
               
                   
                 from available WuXi stock animals. 
               
               
                   
                 Animals will have undergone a physical 
               
               
                   
                 examination for general health by a 
               
               
                   
                 staff veterinarian. 36 males confirmed 
               
               
                   
                 as being healthy will be assigned to study. 
               
               
                 Acclimation Period 
                 Selected animals will be acclimated 
               
               
                   
                 at the WuXi testing facility prior 
               
               
                   
                 to the study. 
               
               
                   
               
            
           
         
       
     
     3.2 Animal Care 
     3.2.1 Environmental Conditions 
     The room(s) will be controlled and monitored for relative humidity (targeted mean range 40% to 70%, and any excursion from this range for more than 3 hours will be documented as a deviation) and temperature (targeted mean range 18° C. to 26° C., and any excursion from this range will be documented as a deviation) with 10 to 20 air changes/hour. The room will be on a 12-hour light/dark cycle except when interruptions are necessitated by study activities. 
     3.2.2 Housing 
     Animals will be pair-housed in cages that are in accordance with applicable animal welfare laws and regulations during acclimation period. The monkeys will be housed individually in cages during experiment. 
     Diet and Feeding 
     Animals will be fed twice daily. Stock monkeys will be fed approximately 120 grams of Certified Monkey Diet daily. These amounts can be adjusted as necessary based on food consumption of the group or body weight changes of an individual and/or changes in the certified diet. 
     Animals will be fasted overnight prior to blood collections for serum chemistry. 
     Administration of Dose Formulation 
     For the administration schedule and sampling also see  FIG.  2     
     
       
         
           
               
               
             
               
                   
               
             
            
               
                 Administration Route: 
                 Subcutaneous injection via the 
               
               
                   
                 dorsal area of the animals&#39; 
               
               
                   
                 thoracic regions. 
               
               
                 Justification for the Dose 
                 Dose levels chosen to characterize 
               
               
                 Level: 
                 the pharmacodynamics of test article 
               
               
                   
                 in monkeys over the desired dose range 
               
               
                   
                 and dosing frequencies. 
               
               
                 Justification for the 
                 This administration route is consistent 
               
               
                 Administration Route: 
                 with the proposed initial route of human 
               
               
                   
                 administration. 
               
               
                 Dose Administration: 
                 The dose formulations will be 
               
               
                   
                 administered per facility SOPs. 
               
               
                   
                 SC ADMINISTRATION: SC injection 
               
               
                   
                 site will be along the dorsal area 
               
               
                   
                 of the animals&#39; thoracic regions. 
               
               
                   
                 When the injection site is altered, the 
               
               
                   
                 location must be documented in the record. 
               
               
                   
               
            
           
         
       
     
     Drinking Water 
     Reverse osmosis (RO) water will be available to all animals, ad libitum. 
     3.2.3 Feed and Water Analyses 
     RO water is analyzed every three months and every batch of feed will be analyzed before use. Feed and water analyses will be maintained in the facility records. 
     3.2.4 Environmental Enrichment 
     Enrichment toys will be provided. 
     4.1 Observations and Examinations 
     4.1.1 Clinical Observations 
     Twice daily (approximately 9:30 a.m. and 4:00 p.m.), cage-side observations for general health and appearance will be conducted. Animals will be given physical examinations prior to study initiation to confirm animals&#39; health. On dosing days, the animals will be observed at 2, 4 and 6-hours post-dosing. General condition, injection site, behavior, activity, excretion, respiration, or other unusual observations noted throughout the study will be recorded in the raw data. When necessary, additional clinical observations will be performed and recorded. A staff veterinarian or veterinary technician will evaluate each animal if clinical observations demonstrate declining animal condition and the Study Director will be notified. The Study Director, or designee, will notify the Sponsor if warranted by the evaluation. 
     4.1.2 Body Weight 
     All animals will be weighed weekly. On dosing days, animals will be weighed prior to dosing. 
     4.1.3 Blood Collection for Clinical Pathology 
     All blood samples will be collected from a peripheral vessel from restrained, non-sedated animals. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Clinical Pathology Schedule 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Sample Volume 
               
               
                   
                   
                 Sampling 
                   
                 Tube Type/Size 
                 approximately 
               
               
                 Groups 
                 Sample 
                 Schedule a   
                 Evaluations 
                 Information 
                 (minimum) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1-9 
                 Blood 
                 Once during 
                 Hematology 
                 K 2 EDTA 
                   2 mL 
                 2.0 mL (1.0 mL) 
               
               
                   
                   
                 pre-study 
                 Clinical 
                 Plain with 
                 1.4 mL 
                 0.7 mL (0.6 mL) 
               
               
                   
                   
                 (Day −16); 
                 Chemistry 
                 separating gel 
               
               
                   
                   
                 Weeks 1, 2, 3, 
               
               
                   
                   
                 4, 6, 8, 10, 13. 
               
               
                   
               
               
                   a Blood sample may be collected from animals subjected to unscheduled euthanasia. Animals may not be fasted under that circumstance. 
               
            
           
         
       
     
     (1) Blood Collection for Hematology: Whole blood (at least 1.0 mL) will be collected from the animals into commercially available tubes with Potassium (K2) EDTA at room temperature (RT). The blood samples will be sent to clinical pathology lab in RT and tested for hematology parameters listed in the Table 8. 
     Erythrocyte count (RBC), Red cell distribution width (RDW), Hematocrit (HCT), Platelet count (PLT), Hemoglobin (HGB), Mean platelet volume (MPV), Mean corpuscular volume (MCV), Leukocyte counts (WBC), and Differential (absolute and percent), Mean corpuscular hemoglobin (MCH), Blood smear for possible cytology, Mean corpuscular hemoglobin concentration (MCHC), Absolute reticulocyte count (Retic), Hemoglobin Concentration Distribution Width (HDW) and Platelet Distribution Width (PDW) 
     A blood smear will be prepared from each hematology sample. Blood smears will be labeled, stained, and stored. Blood smears may be read to investigate results of the hematology analyses. If additional examination of blood smears is deemed necessary, the smears may be evaluated subsequently and this evaluation will be described in a study plan amendment. 
     (2) Blood Collection for Clinical Chemistry: Whole blood samples (approximately 1.4 mL) without anticoagulant will be collected into commercially available plain tubes with separating gel, held at RT up-right for at least 30 minutes, and sent to clinical pathology lab. The samples will be processed to serum, which will be examined for the parameters listed in Table 8. Alkaline Phosphatase (ALP), Total Protein (TP), Alanine Aminotransferase (ALT), Albumin (ALB), Aspartate Aminotransferase (AST), g-glutamyltransferase (GGT), Bilirubin, total (TBIL), Globulin (GLB), Phosphorus (P), Albumin/Globulin Ratio Creatinine (CRE), Sodium (Na), Glucose (GLU), Chloride (CO, Calcium (Ca), Triglycerides (TG), Total Cholesterol (TCHO), Urea (UREA), Potassium (K), Creatine Kinase (CK), Lactate Dehydrogenase (LDH), Glutamate dehydrogenase (GLDH) 
     4.1.4 Blood Collection for Pharmacodynamics (PD) 
     Blood: All blood samples will be collected from a peripheral vessel from restrained, non-sedated animals. 
     Animals: All available, all groups 
     
       
         
           
               
             
               
                 TABLE 10 
               
             
            
               
                   
               
               
                 Pharmacodynamics Schedule 
               
            
           
           
               
               
               
               
               
               
            
               
                   
                   
                   
                   
                   
                 Sample Volume 
               
               
                   
                   
                 Sampling 
                   
                 Tube Type/Size 
                 approximately 
               
               
                 Groups 
                 Sample 
                 Schedule a   
                 Evaluations 
                 Information 
                 (minimum) 
               
               
                   
               
            
           
           
               
               
               
               
               
               
               
            
               
                 1-9 
                 Blood 
                 Once during 
                 CFB ELISA 
                 K 2 EDTA 
                 2 mL 
                 1.5 mL (1.0 mL) 
               
               
                   
                   
                 pre-study 
                 Serum 
                 Plain with 
                 3 mL 
                 1.5 mL (1.3 mL) 
               
               
                   
                   
                 (Day −16); 
                   
                 separating gel 
               
               
                   
                   
                 Day 1, and 
               
               
                   
                   
                 weekly 
               
               
                   
                   
                 thereafter. 
               
               
                   
               
               
                   a Blood sample may be collected from animals subjected to unscheduled euthanasia. Animals may not be fasted under that circumstance. 
               
               
                 Post-Dose 
               
               
                 Blood volume: Approximately 5.0 mL total 
               
            
           
         
       
     
     Frequency: Refer to Table 8. Actual sample collection times will be recorded in the study records. For samples collected within the first hour of dosing, a ±1 minute is acceptable. For the remaining time points, samples that are taken within 5% of the scheduled time are acceptable and will not be considered as protocol deviation. 
     Sample Processing: For CFB ELISA: 2 mL Blood will be collected into a tube (Purchased from sponsor&#39;s required company) containing K2EDTA on wet ice. Then all the blood will be mixed upside down 4 times. Samples will be centrifuged (1000 g for 20 minutes at 4° C.) and approximately 1 mL plasma will be transferred into two tubes quickly (approximately 0.50 mL per tube). All tubes should be flash frozen, and then stored at −80° C. until shipped to WuXi SH site (on dry ice), ATTN: Zhang Ronghua (zhang_rong@wuxiapptec.com) for analysis of CFB protein by ELISA or stored as back up. 
     For Serum: Whole blood samples (approximately 3.0 mL) without anticoagulant will be collected in serum separator tubes. Invert the tubes gently 4 times. Then held at RT and up-right for 30 minutes, to allow clotting, and then samples will be centrifuged (3200 g for 10 minutes at 4° C.) and approximately 1.5 mL serum will be transferred into three tubes quickly (approximately 0.50 mL per tube). one will be shipped to WuXi SH site (on dry ice), ATTN: Zhang Ronghua (zhang_rong@wuxiapptec.com) for analysis of CFB protein by ELISA under 4 C. other two tubes should be flash frozen, and then stored at −80° C. as back up. 
     Protocol Amendments and Deviations 
     Changes to the approved protocol will be in the form of amendments approved by the Study Director and the Sponsor. Amendments will describe the protocol changes clearly and will include the effective date of the change and the justification for the change. The Study Director and Sponsor Representative may authorize protocol changes by telephone or electronic means if he/she is not physically present at the time urgent or critical changes are required. Any authorization for such changes made as above must be documented appropriately and followed by a properly prepared written protocol amendment. The amendment must be signed and dated by the Study Director within 45 days of the effective date(s). 
     All deviations from the protocol and SOPs and the reasons of the deviations will be documented and acknowledged by the Study Director. The Sponsor Representative will be informed promptly of the occurrence of any deviations that might affect the results of the study, and any corrective actions taken. Protocol and SOP deviations that could impact data interpretation will be included in the final report. 
     Archiving of Materials 
     Test article preparation, test article tracking, in-life data, protocol, protocol amendments (if applicable), and the original final report generated as a result of this study will be archived at WuXi AppTec, Wuzhong District, Suzhou, Jiangsu Province 215104, P.R. China. WuXi AppTec will be responsible for archiving any raw data generated as a result of this study and the storage life should be at least 2 years following the date on which the study is completed. 
     Statistical Analysis 
     The following section does not apply to data recorded on unscheduled occasions. Such data will be reported on an individual basis. 
     All numerical data (except those that are collected directly and analyzed by Provantis) will be subjected to calculation of group means and standard deviations by using Microsoft Excel software, unless otherwise stated hereafter. These descriptive statistics will be presented for each dataset of interest, as determined by the variable to be analyzed and the dataset classification variables (for example: sex, measurement occasion, and any other relevant variable that can be used to specify on which subdivision the descriptive statistics have to be reported). 
     If a dataset has fewer than three non-missing values in each group, then the following inferential data analysis will not be conducted. 
     Whenever there are more than two groups, the homogeneity of the group variances will be evaluated using Levene&#39;s test at the 0.05 significance level. If differences between group variances are not found to be significant (p&gt;0.05), then a parametric one-way analysis of variance (ANOVA) will be performed. When significant differences among the means are indicated by ANOVA test (p≤0.05), Dunnett&#39;s test will be used to perform the group mean comparisons between the control group and each treated group. 
     If Levene&#39;s test indicates heterogeneous group variances (p≤0.05) and the data set contains just positive values, log transformation will be performed. If transformed data still fail the test for homogeneity of variance (p≤0.05) or where the data contain zero and/or negative values, then the non-parametric Kruskal-Wallis test will be used to compare all considered groups. When Kruskal-Wallis test is significant (p≤0.05), Dunnett&#39;s test on ranks will be used to perform the pairwise group comparisons of interest. 
     Whenever there are only two groups to compare, Levene&#39;s test will be performed as described above but a two-sample t-test will replace the one-way ANOVA, a Wilcoxon rank-sum test will be performed instead of the Kruskal-Wallis and, no Dunnett&#39;s tests or Dunnett&#39;s tests on ranks will be performed. 
     Each pairwise group comparisons of interest will be conducted via a two-sided test at the 5% significance level. Significant results will be reported as either p≤0.001, p≤0.01, or p≤0.05, where p represents the observed probability. 
     Results 
     Max reduction of Factor Bb and duration of response (see  FIG.  3   a   ):
         106-13(4)
           Max suppression of 74% at week 5   &gt;60% reduction from week 2 to week 13   Mean BLQ from week 2 to week 10   
           13-5
           Max suppression of 59% at week 6   &gt;50% reduction from week 2 to week 13   No Mean BLQ for any of the timepoints   
               

     Max reduction of Factor Bb and duration of response (see  FIG.  3   b   ):
         106-13(4)
           Max suppression of 68% at week 6   &gt;50% reduction from week 4 to week 13   Mean BLQ at week 6   
           13-5
           Max suppression of 68% at week 6   &gt;50% reduction from week 2 to week 13   Mean BLQ from week 6 to week 11   
               

     Example 5 
     Dose Response and Duration Response In Vivo in a Humanized Liver Mouse Model 
     The purpose of this study is to evaluate a dose- and duration-response effect of selected candidate leads for GalNAc-siRNA constructs targeting Complement Factor B (CFB) in a humanized liver UPA-SCID mouse model. Test articles will be administered via subcutaneous administration and evaluated at 14 and 42 days post-dose. Endpoints will include the collection of liver punch biopsies, and the collection of serum and plasma samples for the evaluation of Factor Bb and CFB activity in the Factor Bb ELISA and hemolytic assay, respectively. 
     Materials and Methods 
     Test and Control Articles 
     
       
         
           
               
             
               
                   
               
               
                 Vehicle: Phosphate Buffered Saline (PBS) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Identification 
                 PBS 
               
               
                   
                 Description 
                 Vehicle 
               
               
                   
                 Appearance 
                 Clear solution 
               
               
                   
                 CAS Number 
                 N/A 
               
               
                   
                 Manufacturer/Supplier 
                 Will be documented in study 
               
               
                   
                   
                 records and final report 
               
               
                   
                 Storage Conditions 
                 Ambient 
               
               
                   
                 Catalog Number 
                 Will be documented in study 
               
               
                   
                   
                 records and final report 
               
               
                   
                 Lot/Batch Number 
                 Will be documented in study 
               
               
                   
                   
                 records and final report 
               
               
                   
                 Expiration/Retest Date 
                 Will be documented in study 
               
               
                   
                   
                 records and final report 
               
               
                   
                 Sterility 
                 Sterile 
               
               
                   
                 Purity 
                 Will be documented in study 
               
               
                   
                   
                 records and final report 
               
               
                   
                 pH 
                 Will be documented in study 
               
               
                   
                   
                 records and final report 
               
               
                   
                 Dose Concentration 
                 0 mg/kg 
               
               
                   
                 Dose Volume 
                 200 μL fixed volume 
               
               
                   
                 Route 
                 Subcutaneous injection 
               
               
                   
                 Dosing Frequency 
                 Once on Day 0 
               
               
                   
                 Dose Preparation 
                 N/A 
               
               
                   
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                   
               
               
                 Test Article: CFB mxRNA #13-5 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Identification 
                 CFB - 13-5 
               
               
                 Description 
                 GalNAc-siRNA targeting 
               
               
                   
                 Complement Factor B 
               
               
                 Appearance 
                 Clear liquid 
               
               
                 CAS Number 
                 N/A 
               
               
                 Manufacturer/Supplier 
                 RiboBio 
               
               
                 Storage Conditions 
                 4° C. 
               
               
                 Lot/Batch Number 
                 N/A 
               
               
                 Expiration/Retest Date 
                 N/A 
               
               
                 Sterility 
                 &lt;1 EU/mg 
               
               
                 Purity 
                 &gt;80% 
               
               
                 pH 
                 N/A 
               
               
                 Dose Levels 
                 10 and 30 mg/kg (approximated - 
               
               
                   
                 fixed volumed will be administered) 
               
               
                 Dose Volume 
                 200 μL fixed volume 
               
               
                 Dose Concentrations 
                 N/A 
               
               
                 Route 
                 Subcutaneous injection in scruff 
               
               
                   
                 (Note: that the injection must be 
               
               
                   
                 given subcutaneously. The test articles 
               
               
                   
                 will not be functional if the subcutaneous 
               
               
                   
                 site is missed, and injection is given within 
               
               
                   
                 the muscular region or test articles are injected 
               
               
                   
                 into the vein/bloodstream) 
               
               
                 Dosing Frequency 
                 Once on Day 0 
               
               
                 Dose Preparation 
                 Ready to inject solutions will be provided 
               
               
                   
               
            
           
         
       
     
     
       
         
           
               
             
               
                   
               
               
                 Test Article: CFB mxRNA #106-13(4) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
            
               
                 Identification 
                 CFB - 13-5 
               
               
                 Description 
                 GalNAc-siRNA targeting 
               
               
                   
                 Complement Factor B 
               
               
                 Appearance 
                 Clear liquid 
               
               
                 CAS Number 
                 N/A 
               
               
                 Manufacturer/Supplier 
                 RiboBio 
               
               
                 Storage Conditions 
                 4° C. 
               
               
                 Lot/Batch Number 
                 N/A 
               
               
                 Expiration/Retest Date 
                 N/A 
               
               
                 Sterility 
                 &lt;1 EU/mg 
               
               
                 Purity 
                 &gt;80% 
               
               
                 pH 
                 N/A 
               
               
                 Dose Levels 
                 10 and 30 mg/kg (approximated - 
               
               
                   
                 fixed volumed will be administered) 
               
               
                 Dose Volume 
                 200 μL fixed volume 
               
               
                 Dose Concentrations 
                 N/A 
               
               
                 Route 
                 Subcutaneous injection in scruff 
               
               
                   
                 (Note: that the injection must be 
               
               
                   
                 given subcutaneously. The test articles 
               
               
                   
                 will not be functional if the subcutaneous 
               
               
                   
                 site is missed, and injection is given within 
               
               
                   
                 the muscular region or test articles are injected 
               
               
                   
                 into the vein/bloodstream) 
               
               
                 Dosing Frequency 
                 Once on Day 0 
               
               
                 Dose Preparation 
                 Ready to inject solutions will be provided 
               
               
                   
               
            
           
         
       
     
     Dose Formulation 
     No preparation is required for the test material as it will be received as ready-to-dose formulations. 
     Identification of Test and Control Articles 
     All test article, positive control, and vehicle control storage containers will be labeled at a minimum with identification (including lot/batch number, if available), storage conditions, and expiration/retest date, if available. 
     Test System 
     Justification of Test System 
     Humanized liver uPA-SCID mice are reported to have up to 95% human hepatocyte engraftment; normal human liver histology and function; human-specific metabolism and excretion pathways; expression of human genes, mRNA, and proteins; human-like lipid profiles, production of human albumin and human-like biliary excretion, and a wide range of research applications. Thus, humanized liver uPA-SCID mice are an ideal test system for the evaluation of therapeutics that involve CFB targets as CFB is produced in the liver. 
     Animals 
     Female humanized liver uPA-SCID mice (approximately 22-24 weeks old) were acclimated at least 7 days prior to use. Only animals in good health prior to dosing will be assigned to the study. The animals will be monitored daily for the appearance of local or systemic toxicity. All animals will be housed in clean room and animal handling will be performed in a sterilized biological safety cabinet by trained personnel wearing appropriately disinfected personal protective equipment. 
     Methodology 
     Study Outline 
     On Day 0, all study animals will be dosed by subcutaneous injection according to the Study Outline below. Clinical observations will be recorded daily. The study design will require 32 female mice (4 mice per treatment group, plus 2 extra mice). On Day 14, 4 vehicle animals (Group 1A), 8 CFB mxRNA #13-5 animals (Groups 2A and 2B), and 8 CFB mxRNA #106-13(4) animals (Groups 3A and 3B) will be euthanized. On Day 42, 4 CFB mxRNA #13-5 animals (Group 2C), and 4 CFB mxRNA #106-13(4) animals (Group 3C) will be euthanized. At each timepoint, terminal blood collections for serum and plasma, liver punch biopsies, and the collection of remaining liver tissue will be performed. 
     
       
         
           
               
            
               
                   
               
               
                 Study Outline 1   
               
            
           
           
               
               
               
               
               
            
               
                   
                 Terminal 
                 Control 
                 CFB mxRNA 
                 CFB mxRNA 
               
               
                   
                 Timepoint 
                 (PBS) 
                 #13-5 
                 #106-13(4) 
               
               
                   
                   
               
               
                   
                 Day 14 
                 Group 
                 Group 2A 
                 Group 3A 
               
               
                   
                   
                 1A 
                 (10 mg/kg) 
                 (10 mg/kg) 
               
               
                   
                   
                   
                 Group 2B 
                 Group 3B 
               
               
                   
                   
                   
                 (30 mg/kg) 
                 (30 mg/kg) 
               
               
                   
                 Day 42 
                 Group 
                 Group 2C 
                 Group 3C 
               
               
                   
                 (Week 6) 
                 1B 
                 (10 mg/kg) 
                 (10 mg/kg) 
               
               
                   
                   
               
               
                   
                   1 n = 4/group. Two extra mice will serve as replacements due to health conditions or body weight outliers. 
               
            
           
         
       
     
     Body Weights 
     Body weights will be collected at receipt (for general health assessment), on Day -1, and at terminal timepoints prior to euthanasia. 
     Dosing (Day 0) 
     On Day 0, all mice will be injected subcutaneously with vehicle or test article per the Study Outline Table. Each animal will be injected subcutaneously in scruff with an injection volume of 200 uL. 
     Daily Observations 
     All animals will be observed at least once daily for clinical signs. As humanized mice are predisposed to opportunistic infection due to compromised immune function. Staff will monitor mice for clinical signs that may indicate infection, including ruffled fur and hunched posture that become more pronounced beyond the slightly ruffled fur and hunched posture that exists at baseline, and decreased activity. Common infections to be aware of in these mice include: infected skin wounds, cellulitis, abscesses (skin and internal organs), otitis media, conjunctivitis, panophthalmitis, and localized and widespread infections involving liver, heart, lungs, uterus, accessory sex glands. While not indicative of infection, abdominal distension (related to liver tissue engraftment) may be observed and if observed, will be noted. 
     Unscheduled Deaths and Moribund Animals 
     Moribund animals displaying severe effects will be discussed with the veterinarian or euthanized at the veterinarian&#39;s and Study Director&#39;s recommendation. Animals will be monitored with an increased frequency (up to twice daily; at least 5 hours between observations) if adverse clinical signs are observed, including mortality of other animals on study. Abnormal findings will be recorded as they are observed. 
     Samples will be collected from animals found dead and carcasses will be discarded without further evaluation. 
     Terminal Procedures (Day 14 and Day 42) 
     All mice remaining at the scheduled intervals (Days 14 and 42) will be euthanized by asphyxiation with CO2, and terminal blood collections will be collected via cardiac stick or the inferior vena cava (maximum volume, collection site to be documented in the study records) for processing to serum and plasma. Terminal body weights will be collected prior to euthanasia. 
     Plasma and Serum Processing 
     Following terminal collections on Days 14 and 42, respectively, blood will be processed to plasma for Factor Bb analysis and to serum for the hemolytic assay. Blood sample volumes will be divided evenly for plasma and serum processing. 
     Plasma 
     Blood samples will be placed into K2 EDTA blood collection tubes and inverted 8-10 times to ensure adequate mixing. Samples will be maintained cold, on ice, and centrifuged in an instrument set to 2-4° C. and &lt;1300×g for 10 minutes, within 60 minutes of sample collection. Each plasma sample will be aliquoted into two fresh, labeled collection tubes and stored frozen at ≤−70° C. until analysis is performed. 
     Serum 
     Blood samples will be placed into blood collection tubes without anti-coagulant and allowed to clot for 30-60 minutes. Samples will then be processed to serum following centrifugation at 2500×g for 5 minutes in an instrument set to room temperature. Each serum sample will be aliquoted into a fresh, labeled collection tube and snap-frozen with dry ice immediately following collection. Sample tubes will be labeled with the study number and sample type, and stored at ≤−70° C. until analysis is performed. 
     Organ Processing 
     Three (3) liver punch biopsies (2 mm) will be obtained from each collected liver (taken from the left, middle, and right lobes, respectively) and placed into separate, labeled 2 mL tubes containing RNALater. Liver punch biopsies will be allowed to soak in the RNALater for 15 minutes, then will be flash-frozen and stored at ≤−70° C. 
     Results 
     Mice with humanized liver cells (and retaining about 20 to 25% murine liver cells) have been used to study performance of two specific compounds. 
       FIG.  5    shows an overview of the study protocol. 
       FIG.  6    shows knock-down at the mRNA level by two compounds as compared to negative control after 2 and 6 weeks. 
       FIG.  7    shows amounts of CFB (“Factor B”) as well as of Factor Bb (as further read-out for CFB and complement pathway down-regulation) in plasma as compared to negative control after 2 and 6 weeks. 
     The data demonstrate significant knock-down at both mRNA and protein level for both compounds, where 106-13(4) outperforms 13(5). A certain rebound after six weeks, to a lesser extent for the former compound, can be seen. 
     As regards protein levels, and including component Bb of the complement pathway, an even more persistent knock-down is observed. In particular, compound 106-13(4) shows Bb knock-down in plasma at a level of 64% reduction still after 6 weeks. Such findings are indicative of a favourable dosage regimen requiring administration in large intervals such as every 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks.