Lipid nanoparticles

Abstract

The purpose of the present invention is to provide lipid nanoparticles capable of efficiently introducing a nucleic acid into T cells. Provided are lipid nanoparticles each comprising: a nucleic acid encapsulated in each of the lipid nanoparticles; a cationic lipid; sterol or a sterol derivative; DSPC; a targeted polyalkylene glycol-modified lipid linked to a target binding site; and a non-targeted polyalkylene glycol-modified lipid to which the target binding site is not linked. The target binding site targets a target site on each T cell. The amount of the cationic lipid is 35.0-55.0 mol% with respect to the total lipid amount of the lipid nanoparticles. The amount of sterol is 25.0-40.0 mol% with respect to the total lipid amount of the lipid nanoparticles. The amount of DSPC is 15.0-35.0 mol% with respect to the total lipid amount of the lipid nanoparticles. The N / P ratio is 8.0-12.0.

Description

Lipid nanoparticles

[0001] This disclosure relates to lipid nanoparticles.

[0002] Lipid nanoparticles (LNPs) are used as carriers to encapsulate nucleic acids such as siRNA (small interfering RNA) and mRNA and deliver them to cells. For example, lipid nanoparticles that serve as carriers for efficiently delivering nucleic acids into cells have been reported, and these LNPs contain cationic lipids as constituent lipids that are electrically neutral at physiological pH and change to cationic under weakly acidic pH environments such as endosomes (for example, Patent Document 1).

[0003] Attempts have been made to enable the selective delivery of nucleic acids to target cells. For example, Patent Documents 2 and 3 disclose LNPs formed by linking single-stranded variable fragments (scFv) that target antigens present on the cell surface.

[0004] International Publication No. 2022 / 071582, International Publication No. 2023 / 287861, International Publication No. 2024 / 102772

[0005] Although LNPs have been shown to be effective for the selective delivery of nucleic acids, this remains challenging. Therefore, there is a need for novel lipid nanoparticles that enable the selective delivery of nucleic acids to target cells (T cells in this disclosure) by targeting specific sites on those cells.

[0006] The inventors have completed the present invention by discovering that the lipid nanoparticles in this disclosure enable the selective delivery of nucleic acids to target cells, namely T cells.

[0007] This disclosure includes one or more embodiments described below: [1] Lipid nanoparticles comprising: nucleic acid encapsulated in the lipid nanoparticles; cationic lipids; sterols or sterol derivatives; DSPCs; targeted polyalkylene glycol-modified lipids linked to a target binding site; and untargeted polyalkylene glycol-modified lipids not linked to a target binding site, wherein the target binding site targets a target site on a T cell; the amount of cationic lipids is 35.0 to 55.0 mol% of the total lipid amount of the lipid nanoparticles; the amount of sterols is 25.0 to 40.0 mol% of the total lipid amount of the lipid nanoparticles; the amount of DSPCs is 15.0 to 35.0 mol% of the total lipid amount of the lipid nanoparticles; and the N / P ratio is 8.0 to 12.0. [2] The lipid nanoparticles according to [1], wherein the N / P ratio is 9.0 to 11.0. [3] The lipid nanoparticle according to [1] or [2], wherein the sum of the targeted polyalkylene glycol-modified lipid and the untargeted polyalkylene glycol-modified lipid is 1.0 to 2.2 mol% of the total lipid amount of the lipid nanoparticle. [4] The lipid nanoparticle according to any one of [1] to [3], wherein the sum of the polyalkylene glycol-modified lipid linked to a target binding site and the polyalkylene glycol-modified lipid not linked to a target binding site is 1.0 to 1.8 mol% of the total lipid amount of the lipid nanoparticle. [5] The lipid nanoparticle according to any one of [1] to [4], wherein the target site on the T cell is CD2, CD3, CD4, CD5, CD6, CD7, or CD8. [6] The lipid nanoparticle according to any one of [1] to [5], wherein the target site on the T cell is CD8. [7] The lipid nanoparticle according to any one of [1] to [6], wherein the target binding site is an antibody or its antigen-binding fragment. [8] The lipid nanoparticle according to any one of [1] to [7], wherein the target binding site is an antibody, a Fab fragment, a Fab' fragment, an F(ab')2 fragment, scFv, or a VHH antibody. [9] The lipid nanoparticle according to any one of [1] to [8], wherein the target binding site is a VHH antibody.

[10] The lipid nanoparticle according to any one of [1] to [9], wherein the sterol or sterol derivative is cholesterol.

[11] The lipid nanoparticle according to any one of [1] to

[10] , wherein the ratio of the targeted polyalkylene glycol-modified lipid to the total of the targeted polyalkylene glycol-modified lipid and the untargeted polyalkylene glycol-modified lipid is greater than 0% and 60% or less.

[12] The lipid nanoparticle according to any one of [1] to

[11] , wherein the ratio of the targeted polyalkylene glycol-modified lipid to the total of the targeted polyalkylene glycol-modified lipid and the untargeted polyalkylene glycol-modified lipid is greater than 0% and 15% or less.

[13] The lipid nanoparticle according to any one of [1] to

[12] , wherein the amount of the cationic lipid is 40.0 mol% of the total lipid amount of the lipid nanoparticle, the amount of the sterol or sterol derivative is 38.5 mol% of the total lipid amount of the lipid nanoparticle, the amount of the DSPC is 20.0 mol% of the total lipid amount of the lipid nanoparticle, and the sum of the polyalkylene glycol-modified lipids linked to the target binding site and the polyalkylene glycol-modified lipids not linked to the target binding site is 1.5 mol% of the total lipid amount of the lipid nanoparticle.

[14] The lipid nanoparticle according to any one of [1] to

[12] , wherein the amount of the cationic lipid is 40.0 mol% of the total lipid amount of the lipid nanoparticle, the amount of the sterol or sterol derivative is 28.5 mol% of the total lipid amount of the lipid nanoparticle, the amount of the DSPC is 30.0 mol% of the total lipid amount of the lipid nanoparticle, and the sum of the polyalkylene glycol-modified lipids linked to the target binding site and the polyalkylene glycol-modified lipids not linked to the target binding site is 1.5 mol% of the total lipid amount of the lipid nanoparticle.

[15] The lipid nanoparticle according to any one of [1] to

[12] , wherein the amount of the cationic lipid is 50.0 mol% of the total lipid amount of the lipid nanoparticle, the amount of the sterol or sterol derivative is 28.5 mol% of the total lipid amount of the lipid nanoparticle, the amount of the DSPC is 20.0 mol% of the total lipid amount of the lipid nanoparticle, and the sum of the polyalkylene glycol-modified lipid linked to the target binding site and the polyalkylene glycol-modified lipid not linked to the target binding site is 1.5 mol% of the total lipid amount of the lipid nanoparticle.

[16] The lipid nanoparticle according to any one of [1] to

[15] , wherein the targeted polyalkylene glycol-modified lipid contains DSPE-PEG, and the untargeted polyalkylene glycol-modified lipid contains DMG-PEG.

[17] The lipid nanoparticle according to any one of [1] to

[16] , wherein the target binding site is linked to the polyalkylene glycol of the targeted polyalkylene glycol-modified lipid via a linker.

[18] The linker is a lipid nanoparticle according to

[17] comprising a peptide of 1 to 50 units.

[19] The linker is (Ser-Ser-Ser-Gly). m (Sequence ID 1) [wherein m is an integer from 1 to 5], (Glu-Ala-Ala-Ala-Lys) n (Sequence No. 2) [wherein n is an integer from 1 to 4], (Ala-Pro) ｐ [In the formula, p is an integer from 1 to 8], (His) ｑ Lipid nanoparticles according to

[17] or

[18] , comprising at least one of the following: [wherein q is an integer from 1 to 10].

[20] The linker is (OCH ２ CH ２ ) ｒ Lipid nanoparticles according to any one of

[17] to

[19] , comprising [wherein r is an integer from 1 to 10].

[21] The linker is of the following formula: Lipid nanoparticles according to any one of

[17] to

[20] , comprising a site represented by [wherein the formula, the left arrow indicates linkage with the peptide, the right arrow indicates linkage with polyalkylene glycol, X is N or O, and r is an integer from 1 to 15].

[22] The linker is represented as -Z1-Z2-, where Z1 is linked to the target binding site, Z2 is linked to the polyalkylene glycol, and Z1 is It is represented as, and Z2 is, A lipid nanoparticle according to any one of

[17] to

[21] , represented by the formula [wherein the left arrow indicates linkage to the adjacent Lys side chain amino group, the right arrow indicates linkage to the polyalkylene glycol, X is N or O, and r is an integer from 1 to 15].

[23] The linker is represented as -Z1-Z2-, where Z1 is linked to the target binding site, Z2 is linked to the polyalkylene glycol, and Z1 is as follows: Z2 is one of the polypeptides shown, and Z2 is A lipid nanoparticle according to any one of

[17] to

[21] , represented by the formula [wherein the left arrow indicates linkage to the adjacent Cys side chain SH group, the right arrow indicates linkage to polyalkylene glycol, and X is N or O].

[24] The untargeted polyalkylene glycol-modified lipid comprises a polyalkylene glycol-modified lipid in which polyalkylene glycol is modified with a reactive group, and a polyalkylene glycol-modified lipid in which polyalkylene glycol is unmodified, according to any one of [1] to

[24] .

[25] The lipid nanoparticle according to

[24] , wherein the reactive group comprises a group selected from the group consisting of acetylene, transcyclooctene, cyclooctin, diarylcyclooctin, oxime, ketone, aldehyde, thiol, free cysteine, amine, maleimide, NHS (N-hydroxysuccinimide), NHS ester (N-hydroxysuccinimide ester), isocyanate, isothiocyanate, methyl ester phosphine, norbornene, tetrazine, methylcyclopropene, azetine, cyanide, azide, and dibenzocyclooctin.

[26] The lipid nanoparticle according to

[24] or

[25] , wherein the reactive group comprises maleimide.

[27] The lipid nanoparticle according to any one of

[24] to

[26] , wherein the polyalkylene glycol-modified lipid, in which polyalkylene glycol is modified with a reactive group, comprises DSPE-PEG, and the polyalkylene glycol-modified lipid, in which polyalkylene glycol is unmodified, comprises DMG-PEG.

[28] The lipid nanoparticle according to any one of [1] to

[23] , comprising: a polyalkylene glycol-modified lipid having polyalkylene glycol modified at a non-targeting site; and a polyalkylene glycol-modified lipid having no polyalkylene glycol modification.

[29] The lipid nanoparticle according to

[28] , wherein the polyalkylene glycol-modified lipid having polyalkylene glycol modified at a non-targeting site contains DSPE-PEG, and the polyalkylene glycol-modified lipid having no polyalkylene glycol modification contains DMG-PEG.

[30] Lipid nanoparticles according to any one of [1] to

[29] , wherein the nucleic acid is siRNA, antisense nucleic acid, heteroduplex nucleic acid, miRNA, gRNA, or mRNA.

[0008] The lipid nanoparticles of the present invention can selectively deliver nucleic acids to target cells, namely T cells. In particular, the present invention can selectively deliver nucleic acids to T cells compared to the liver.

[0009] Figure 1 shows that antibody-conjugated LNPs 1g to 8g in Example 1 are carriers capable of selectively delivering mRNA to CD8-positive T cells. Figure 2 shows the liver delivery capabilities of antibody-conjugated LNPs 1g to 8g in Example 1. Figure 3 shows the relative ratios of (T cell delivery capability / liver delivery capability) for antibody-conjugated LNPs 2g to 8g, with the ratio of (T cell delivery capability / liver delivery capability) for antibody-conjugated LNP 1g in Example 1 set to 1.0. In particular, antibody-conjugated LNP 4g shows high T cell selectivity. Figure 4 shows the relative ratios of corresponding LNPs 2a, 4a, 6a, and 8a in Example 2, with the ratios of (T cell delivery capability / liver delivery capability) for antibody-conjugated LNPs 1a, 3a, 5a, and 7a each set to 1.0. Figure 5 shows the relative ratios of LNP3b, 4b, 7b, 8b, and 9b in Example 3, when the ratio of (T cell deliverability / liver deliverability) of antibody-conjugated LNP 5b is set to 1.0. Figure 6 shows the relative ratios of LNP13b, 14b, 17b, 18b, and 19b in Example 3, when the ratio of (T cell deliverability / liver deliverability) of antibody-conjugated LNP 15b is set to 1.0. Figure 7 shows the relative ratios of LNP23b, 24b, 27b, 28b, and 29b in Example 3, when the ratio of (T cell deliverability / liver deliverability) of antibody-conjugated LNP 25b is set to 1.0. Figure 8 shows the mCherry expression rate in T cells 24 hours after administration of antibody-conjugated LNP to mice in Example 4. Figure 9 shows the mCherry MFI in T cells 24 hours after administration of antibody-conjugated LNP to mice in Example 4. Figure 10 shows the mCherry expression rate in T cells 24 hours after administration of antibody-conjugated LNP to mice in Example 5. Figure 11 shows the mCherry MFI in T cells 24 hours after administration of antibody-conjugated LNP to mice in Example 5. Figure 12 is a schematic diagram showing one embodiment of the method for producing lipid nanoparticles of the present invention.

[0010] The lipid nanoparticles of the present invention include nucleic acids, cationic lipids, and targeted polyalkylene glycol-modified lipids. In this disclosure, the term “lipid nanoparticles (LNPs)” means particles comprising multiple lipid molecules physically bound to one another by intermolecular forces. Lipid nanoparticles may be, for example, microspheres (including monolayer and multilayer vesicles, e.g., liposomes), dispersed phases in emulsions, micelles, or internal phases in suspensions.

[0011] 1. Nucleic Acids The lipid nanoparticles according to the present invention preferably contain a component intended for delivery into target cells within a lipid membrane-covered particle. The component contained within the lipid nanoparticles according to the present invention is not particularly limited as long as it is of a size that can be encapsulated. Any substance such as nucleic acids, sugars, peptides, low molecular weight compounds, and metal compounds can be encapsulated in the lipid nanoparticles according to the present invention.

[0012] The nucleic acid encapsulated in the lipid nanoparticles according to the present invention is preferably a functional nucleic acid that controls the expression of a target gene present in the target cell. Examples of such functional nucleic acids include antisense nucleic acids (antisense oligonucleotides, antisense DNA, antisense RNA), heteroduplex nucleic acids, siRNA, microRNA (miRNA), mRNA, guide RNA (gRNA), etc. Alternatively, it may be plasmid DNA (pDNA) that serves as an siRNA expression vector for expressing siRNA in cells. The siRNA expression vector can be prepared from a commercially available siRNA expression vector, or it may be modified as appropriate.

[0013] The gene expression vector to be encapsulated in the lipid nanoparticles according to the present invention is not particularly limited, and vectors commonly used in gene therapy and the like can be used. Preferably, the gene expression vector to be encapsulated in the lipid nanoparticles according to the present invention is a nucleic acid vector such as a plasmid vector. The plasmid vector may remain circular, or it may be pre-cut into a linear shape before being encapsulated in the lipid nanoparticles according to the present invention. The gene expression vector can be designed by conventional methods using commonly used molecular biological tools based on the base sequence information of the gene to be expressed, and can be manufactured by various known methods.

[0014] When the nucleic acid to be encapsulated is mRNA, in one embodiment, the mRNA includes a miRNA binding site. miRNA (microRNA) is typically a small, non-coding single-stranded RNA molecule about 20–25 nucleotides long, produced from hairpin RNA precursors (pre-miRNA), and can form functional complexes with proteins. Typically, miRNA further binds to the UTR region of target mRNA as a functional complex with a protein, and can regulate the target gene by, but not limited to, mRNA degradation or translation inhibition or repression. One embodiment of the miRNA binding site is the miR 122-5p binding site, which can regulate protein expression in hepatocytes.

[0015] In this disclosure, the terms “nucleic acid,” “nucleic acid molecule,” “oligonucleotide,” “polynucleotide,” and “nucleotide” may be used interchangeably. These terms refer to polymers of deoxyribonucleotides (DNA), ribonucleotides (RNA), and their modified forms, which are used as distinct fragments or components of a larger structure, linear or branched, single-stranded, double-stranded, triple-stranded, or hybrids thereof. The term also includes RNA / DNA hybrids. Polynucleotides may include sense and antisense oligonucleotides or polynucleotide sequences of DNA or RNA. DNA or RNA molecules may be, but are not limited to, complementary DNA (cDNA), genomic DNA, synthetic DNA, recombinant DNA, or hybrids thereof, mRNA (including linear and circular mRNA), gRNA, shRNA, siRNA, miRNA, antisense RNA, and other RNA molecules. Furthermore, these terms may include oligonucleotides composed of native bases, sugars, and nucleoside-to-nucleoside covalent bonds, as well as oligonucleotides having non-native parts that function similarly to their respective native parts.

[0016] 2. Cationic Lipids As used herein, “cationic lipids” include ionizable cationic lipids and permanently cationic lipids. As used herein, the term “ionizable cationic lipids” refers to lipids that contain an ionizable moiety capable of becoming positively charged under specific conditions (e.g., a specific pH range, e.g., physiological conditions), and is synonymous with “pH-sensitive cationic lipids.” The ionizable moiety may consist of an amine. In addition to the ionizable moiety, ionizable cationic lipids may contain alkyl or alkenyl groups. As used herein, the term “permanently cationic lipids” refers to lipids that consist of a cationic moiety that is positively charged over any pH range. The permanently cationic moiety may consist of a quaternary amine. In addition to the cationic moiety, permanently cationic lipids may contain alkyl or alkenyl groups. Examples of cationic lipids that constitute the lipid nanoparticles of the present invention are not particularly limited, but include, for example, N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(I-(2,3-dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTAP), N-(I-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), N,N-dimethyl-2,3-dioleyloxy)propylamine (DODMA), 1,2-DiLinoleyloxy-N,N-dimethylaminopropane (DLinDMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 1,2-Dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2-Dilinoleyoxy-3-(dimethylamino)acetoxypropane (DLin-DAC), 1,2-Dilinoleyoxy-3-morpholinopropane (DLin-MA), 1,2-Dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-Dilinoleylthio-3-dimethylaminopropane (DLin-S-DMA), 1-Linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-Dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2-Dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2-Dilinoleyloxy-3-(N-methylpiperazino)propane (DLin-MPZ), または 3-(N,N-Dilinoleylamino)-1,2-propanediol (DLinAP), 3-(N,N-Dioleylamino)-1,2-propanedio (DOAP), bis(3-pentyloctyl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate, 1,2-Dilinoleyloxo-3-(2-N,N-dimethylamino)ethoxypropane (DLin-EG-DMA), 1,2-Dilinolenyloxy-N,N-dimethylaminopropane (DLinDMA), 2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA) またはそのアナログ, (3aR,5s,6aS)-N,N-dimethyl-2,2-di((9Z,12Z)-octadeca-9,12-dienyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-5-amine (ALN100), (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (MC3), 1,1′-(2-(4-(2-((2-(bis(2-hydroxydodecyl)amino)ethyl)(2-hydroxydodecyl)amino)ethyl)piperazin-1-yl)ethylazanediyl)didodecan-2-ol (Tech G1), 9-Heptadecanyl 8-{(2-hydroxyethyl)[6-oxo-6-(undecyloxy)hexyl]amino}octanoate (SM-102), [(4-Hydroxybutyl)azanediyl]di(hexane-6,1-diyl)bis(2-hexyldecanoate) (ALC-0315) , . 2-(bis(2-(tetradecanoyloxy)ethyl)amino)-N-(2-hydroxyethyl)-N,N-dimethyl-2-oxoethane-amino bromide (HEDC), ((2-((2-(dimethylamino)ethyl)thio)acetyl)azanediyl)bis(ethane-2,1-diyl)ditetradecanoate (S104), ((2-(3,4-dihydroxypyrrolidin-1-yl)acetyl)azanediyl)bis(ethane-2,1-diyl)(9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate), ((2-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)acetyl)azanediyl)bis(ethane-2,1-diyl) (9Z,9'Z,12Z,12'Z)-bis(octadeca-9,12-dienoate) and the present invention is disclosed in US Pat. Nos. 9,011,903; 9,308,267;Disclosed in 253, WO2022071582, WO2024226958, PCT / JP2025 / 008116, PCT / US2025 / 020674, PCT / US2025 / 037324, and PCT / JP2025 / 23942, which are incorporated herein by reference. The cationic lipid constituting the lipid nanoparticles according to the present invention may be one type or two or more types.

[0017] 3. Target Binding Sites In this disclosure, the term “target binding site” refers to any type of molecule or part thereof that is limited to a specific cell or can specifically recognize and interact with / bind to (i.e., “target”) a target molecule on the cell surface (also called a “target site,” e.g., a cell surface antigen) that is concentrated on a specific cell. In some embodiments, the target binding site is selected from, but is not limited to, antibodies, antigen-binding fragments, peptides, nucleotides, ligands, ligand mimetic products, agonists and / or antagonists. In some embodiments, the target binding site may be any type of antibody or its antigen-binding fragment. In some embodiments, the target binding site may be an antibody, Fab', F(ab') ２ This includes Fab, Fv, rIgG, scFv, hcAbs (heavy chain antibodies), single-domain antibodies, VHH, VNAR, sdAbs, nanobodies, receptor ectodomains or their ligand-binding portions, or ligands (e.g., cytokines, chemokines), cell marker ligands, receptor ligands, peptides (artificial polypeptides), peptide aptamers, nucleic acids, nucleic acid aptamers, Spiegelmers, or combinations thereof.

[0018] In this disclosure, the term “target site” refers to a biomolecule including a specific protein, peptide, glycan, nucleic acid, or a complex thereof. A target site may be an antigen, cell surface receptor, enzyme active site, or intracellularly localized molecule.

[0019] In the present disclosure, the term "antigen" refers to a molecule or a part of a molecule to which an antibody can specifically bind. An antigen can have one or more epitopes. In some embodiments, the antigen is a protein specifically expressed by a particular cell. In some embodiments, the antigen is a membrane protein. In some embodiments, the antigen is expressed on the outer membrane of a cell. In some embodiments, the antigen is a cell surface protein. In some embodiments, the antigen is a cell surface receptor.

[0020] In a preferred embodiment of the present disclosure, the antigen on the T cell is CD2, CD3, CD4, CD5, CD6, CD7, or CD8.

[0021] In the present disclosure, the term "antibody" is used in the broadest sense and includes monoclonal antibodies (e.g., full-length or intact monoclonal antibodies), polyclonal antibodies, multivalent antibodies, multispecific antibodies (e.g., bispecific antibodies), and antigen-binding fragments of a length sufficient to exhibit the desired binding / recognition activity. An "antigen-binding fragment" is composed of a part of a complete antibody and usually includes the antigen-binding site of the complete antibody, and thus retains the ability to bind to an antigen. In some embodiments, the antigen-binding fragment includes, but is not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, scFv, or VHH antibodies.

[0022] Examples of the antibody or antigen-binding fragment include all or part of polyclonal antibodies, monoclonal antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, bispecific antibodies, minibodies, and linear antibodies.

[0023] In a preferred embodiment of the present invention, the target binding site is a single-chain antibody (e.g., scFv or VHH).

[0024] From the perspective of production reproducibility and / or scale-up, in a more preferred embodiment of the present invention, the target binding site is scFv or VHH.

[0025] In one embodiment of the present invention, the antibody has at least one, preferably all, CDR sequences (according to Kabat nomenclature) selected from the group consisting of DYAIG (SEQ ID NO: 16), CIRIFDRHTYSADSVKG (SEQ ID NO: 17), and GSFWACTRPEGAMDY (SEQ ID NO: 18).

[0026] In one embodiment of the present invention, the antibody has at least one, preferably all, CDR sequences (according to IMGT nomenclature) selected from the group consisting of GSTFSDYG (SEQ ID NO: 19), IDWNGEHT (SEQ ID NO: 20), and AADALPYTVRKYNY (SEQ ID NO: 21).

[0027] In one embodiment of the present invention, the antibody has at least one, preferably all, CDR sequences selected from the group consisting of DFGMN (SEQ ID NO: 22), LIYYDGSNKFYADSVKG (SEQ ID NO: 23), PHYDGYYHFFDS (SEQ ID NO: 24), KGSQDINNYLA (SEQ ID NO: 25), NTDILHT (SEQ ID NO: 26), and YQYNNGYT (SEQ ID NO: 27).

[0028] In one embodiment of the present invention, the antibody has at least one, preferably all, CDR sequences selected from the group consisting of GFIFSNYG (SEQ ID NO: 28), IWYDGSNK (SEQ ID NO: 29), ARSYDMLTGSGDYYGL (SEQ ID NO: 30), QDITNY (SEQ ID NO: 31), GAS (SEQ ID NO: 32), and QQYNNYPLT (SEQ ID NO: 33).

[0029] In one embodiment of the present invention, the antibody has at least one, preferably all, CDR sequences selected from the group consisting of GYTFTNYG (SEQ ID NO: 34), INTHTGEP (SEQ ID NO: 35), TRRGYDWYFDV (SEQ ID NO: 36), QDINSY (SEQ ID NO: 37), RAN (SEQ ID NO: 38), and QQYDESPWT (SEQ ID NO: 39).

[0030] In one embodiment of the present invention, the antibody has at least one, preferably all, CDR sequences selected from the group consisting of GDTICISA (SEQ ID NO: 40), ITSGGST (SEQ ID NO: 41), and NADIAGHNCSGYLKEY (SEQ ID NO: 42).

[0031] In one embodiment of the present invention, the antibody has at least one, preferably all, CDR sequences selected from the group consisting of GFTFNKYA (SEQ ID NO: 43), IRSKYNNYAT (SEQ ID NO: 44), VRHGNFGNSYISYWAY (SEQ ID NO: 45), TGAVTSGNY (SEQ ID NO: 46), GTK (SEQ ID NO: 47), and VLWYSNRWV (SEQ ID NO: 48).

[0032] In one embodiment of the present invention, the antibody has at least one sequence selected from the group consisting of GYTFTSYV (SEQ ID NO: 49), INPYNDGT (SEQ ID NO: 50), AREKDNYATGAWFAY (SEQ ID NO: 51), QSLLYSTNQKNY (SEQ ID NO: 52), WAS (SEQ ID NO: 53), and QQYYSYRT (SEQ ID NO: 54).

[0033] In one embodiment of the present invention, the antibody has at least one, preferably all, CDR sequences selected from the group consisting of GFTFSTFP (SEQ ID NO: 55), LSPSGDST (SEQ ID NO: 56), TKVGFTTFYFDS (SEQ ID NO: 57), QNINKY (SEQ ID NO: 58), NIN (SEQ ID NO: 59), and LQHRTGWT (SEQ ID NO: 60).

[0034] In one embodiment of the present invention, the antibody is antibody 1 represented by the following sequence. The underlined portion indicates the CDR sequence. EVQLVESGGGLVQAGGSLRLSCAASGFTFDDYAIGWFRQAPGKGREGVLCIRIFDRHTYSADSVKGRFTISSDNAQNTVYLHMNSLKPEDTAVYYCAAGSFWACTRPEGAMDYWGKGTQVTVSS (Sequence ID 61)

[0035] In one embodiment of the present invention, the antibody is antibody 2 represented by the following sequence. The underlined portion indicates the CDR sequence. EVQLVESGGGLVQAGGSLRLSCAASGSTFSDYGVGWFRQAPGKGREFVADIDWNGEHTSYADSVKGRFATSRDNAKNTAYLQMNSLKPEDTAVYYCAADALPYTVRKYNYWGQGTQVTVSS (Sequence ID 62)

[0036] In one embodiment of the present invention, the antibody is antibody 3 represented by the following sequence. The underlined portion indicates the CDR sequence. QVQLVESGGGVVQPGRSLRLSCAASGFTFSDFGMNWVRQAPGKGLEWVALIYYDGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPHYDGYYHFFDSWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKGSQDINNYLAWYQQKPGKAPKLLIYNTDILHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCYQYNNGYTFGQGTKVEIK (Sequence ID 63)

[0037] In one embodiment of the present invention, the antibody is antibody 4 represented by the following sequence. The underlined portion indicates the CDR sequence. QVQLVESGGGVVQPGRSLRLSCAASGFTFSDFGMNWVRQAPGKGLEWVALIYYDGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPHYDGYYHFFDSWGQGTLVTVSSSPNSASHSGSAPQTSSAPGSQDIQMTQSPSSLSASVGDRVTITCKGSQDINNYLAWYQQKPGKAPKLLIYNTDILHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCYQYNNGYTFGQGTKVEIK (Sequence ID 64)

[0038] In one embodiment of the present invention, the antibody is antibody 5 represented by the following sequence. The underlined portion indicates the CDR sequence. QVQLVESGGGVVQPGRSLRLSCAASGFTFSDFGMNWVRQAPGKGLEWVALIYYDGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPHYDGYYHFFDSWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKGSQDINNYLAWYQQKPGKAPKLLIYNTDILHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCYQYNNGYTFGQGTKVEIK (Sequence ID 65)

[0039] In one embodiment of the present invention, the antibody is antibody 6 represented by the following sequence. The underlined portion indicates the CDR sequence. QVQLVESGGGVVQPGRSLRLSCAASGFTFSDFGMNWVRQAPGKCLEWVALIYYDGSNKFYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPHYDGYYHFFDSWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCKGSQDINNYLAWYQQKPGKAPKLLIYNTDILHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCYQYNNGYTFGCGTKVEIK (Sequence ID 66)

[0040] In one embodiment of the present invention, the antibody is antibody 7 represented by the following sequence. The underlined portion indicates the CDR sequence. QVQLVESGGGVDQPGRSLRLSCAASGFIFSNYGIHWVRQAPGKGLEWVAVIWYDGSNKYFEDSVKGRFNISRDNSKNIVYLQMNSLRAEDTAVYFCARSYDMLTGSGDYYGLDVWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQDITNYLAWFQQKPGKAPKSLIYGASSLQSGVPSKFSGSGSGTDFTLTISSLQPEDFATYYCQQYNNYPLTFGGGTKVEIK (Sequence ID 67)

[0041] In one embodiment of the present invention, the antibody is antibody 8 represented by the following sequence. The underlined portion indicates the CDR sequence. NIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLRWMGWINTHTGEPTYADDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCTRRGYDWYFDVWGAGTTVTVSSGGGGSGGGGSGGGGSDIKMTQSPSSMYASLGERVTITCKASQDINSYLSWFHHKPGKSPKTLIYRANRLVDGVPSRFSGSGSGQDYSLTISSLDYEDMGIYYCQQYDESPWTFGGGTKLEMK (Sequence ID 68)

[0042] In one embodiment of the present invention, the antibody is antibody 9 represented by the following sequence. The underlined portion indicates the CDR sequence. EVQVVESGGGLVQAGGSLRLSCAASGDTICISAMYWYRQAPGKAREMVAAITSGGSTYYEDSVMGRFTIFRENAKNTVYLQMNSLKPEDTAVYYCNADIAGHNCSGYLKEYWGQGTQVTVSA (Sequence ID 69)

[0043] In one embodiment of the present invention, the antibody is antibody 10 represented by the following sequence. The underlined portion indicates the CDR sequence. EVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWAYWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGNYPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLWYSNRWVFGGGTKLTVLGQPKS (Sequence ID 70)

[0044] In one embodiment of the present invention, the antibody is antibody 11 represented by the following sequence. The underlined portion indicates the CDR sequence. QVQLQQSGPEVVKPGASVKMSCKASGYTFTSYVIHWVRQKPGQGLDWIGYINPYNDGTDYDEKFKGKATLTSDTSTSTAYMELSSLRSEDTAVYYCAREKDNYATGAWFAYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERVTMNCKSSQSLLYSTNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSVQAEDVAVYYCQQYYSYRTFGGGTKLEIK (Sequence ID 71)

[0045] In one embodiment of the present invention, the antibody is antibody 12 represented by the following sequence. The underlined portion indicates the CDR sequence. EVYLVESGGGLVQPGGSVKLSCSASGFTFSTFPMAWVRQAPTQGLQWVATLSPSGDSTYYRDSVKGRFTISRDNVLNTLYLHMDILRSEDTATYYCTKVGFTTFYFDSWGQGVMVAVSSAGGGGSGGGGSGGGGSDIQMTQSPSFLSASVGDRVTINCKASQNINKYLDWYQQKFGETPKLLIYNINNLHSGVPSRFSGSGSGPDFTLTISSLQPEDVATYFCLQHRTGWTFGGGTKVELRRA (Sequence ID 72)

[0046] In a preferred embodiment of the present invention, the target binding site is a single-domain antibody.

[0047] In a preferred embodiment of the present invention, the single-domain antibody is a VHH antibody or a VNAR antibody. In a certain embodiment of the present invention, the target binding site is an artificial polypeptide. In a certain embodiment of the present invention, the artificial polypeptide is DARPin, adnectin, ancarin, and an aphibody.

[0048] In this disclosure, "VHH antibody" (variable domain of heavy chain of heavy chain antibody) refers to a domain containing the variable region of a heavy chain antibody without a light chain, found in the serum of camelid animals (such as Bactrian camels, dromedary camels, llamas, and alpacas). VHH antibodies are known as the smallest unit of immunoglobulin fragments that can bind to an antigen.

[0049] In this disclosure, “T cells (T lymphocytes)” are, for example, major cells of the immune system produced in the bone marrow and matured in the thymus. T cells may recognize antigens presented by antigen-presenting cells (APCs) via T cell receptors (TCRs) and induce specific immune responses. T cells have subtypes such as cytotoxic T cells (CD8-positive T cells), helper T cells (CD4-positive T cells), and regulatory T cells (Tregs). Cytotoxic T cells may directly attack and destroy infected cells or tumor cells. Helper T cells may activate other immune cells and modulate the immune response. Helper T cells can activate B cells to promote antibody production and assist in infection control. Regulatory T cells (Tregs) can suppress excessive immune responses and contribute to the prevention of autoimmune diseases. T cells may be used in cancer immunotherapy, such as CAR-T cell therapy. In CAR-T cell therapy, patient-derived T cells are genetically modified to express CARs (chimeric antigen receptors) that target specific antigens, and then reinjected into the patient to attack cells possessing those specific antigens (ex-vivo CAR-T therapy). Alternatively, patient T cells can be genetically modified within the body to express CARs that target specific antigens, thereby attacking cells possessing those specific antigens (in-vivo CAR-T therapy).

[0050] In a preferred embodiment of the present invention, the target binding site binds to (targets) CD2, CD3, CD4, CD5, CD6, CD7, or CD8, which are target sites on T cells.

[0051] CD2, CD3, CD4, CD5, CD6, CD7, and CD8 are membrane proteins expressed on the surface of immune cells and may be used as markers indicating the function or characteristics of specific immune cells. CD2, CD3, CD4, CD5, CD6, CD7, and CD8 play important roles in the regulation or signal transduction of immune responses. CD2 may be expressed on T cells and innate lymphoid cells, for example, and may be involved in cell adhesion and assisting T cell activation. CD3 may constitute part of the T cell receptor (TCR) complex and be responsible for signal transduction after antigen recognition. CD4 may be specifically expressed on helper T cells and may be an auxiliary molecule necessary for antigen recognition from antigen-presenting cells via MHC class II molecules. CD4 may be used in the evaluation of immune function and in cell fractionation in cell therapy. CD5 is mainly expressed on T cells and some B cells and may contribute to the suppression of autoreactivity by regulating TCR signaling. CD6 may interact with CD5 and play a role in regulating T cell activation and immune synapse formation. CD7 may be expressed on T cells or NK cells and may be involved in cell development and differentiation, as well as assisting in intercellular interactions. CD8 may be specifically expressed on cytotoxic T cells and may function to recognize endogenous antigens (e.g., virus-derived antigens) via MHC class I molecules.

[0052] In one embodiment, when the target molecule (target site) is CD8, the target binding site is a VHH antibody represented by SEQ ID NO: 92 (Antibody 1) or SEQ ID NO: 93 (Antibody 2).

[0053] 4. Polyalkylene glycol-modified lipids: Polyalkylene glycols are hydrophilic polymers, and by using polyalkylene glycol-modified lipids as lipid membrane constituents to construct lipid nanoparticles, the surface of the lipid nanoparticles can be modified with polyalkylene glycol. Surface modification with polyalkylene glycol may improve the stability of lipid nanoparticles, such as their retention in the bloodstream.

[0054] Examples of polyalkylene glycols include polyethylene glycol, polypropylene glycol, polytetramethylene glycol, and polyhexamethylene glycol. The molecular weight of the polyalkylene glycol is, for example, about 200 to 10,000, for example, about 300 to 10,000, preferably about 500 to 10,000, and more preferably about 1,000 to 5,000. In one embodiment of the present invention, the molecular weight of the polyalkylene glycol is about 200, about 300, about 350, about 400, about 500, about 550, about 750, about 1,000, about 1,500, about 2,000, about 3,000, about 3,500, about 4,000, about 5,000, or about 10,000 Da.

[0055] For example, stearylated polyethylene glycol (e.g., PEG-45 stearate (STR-PEG45)) can be used for modifying lipids with polyethylene glycol. Other options include N-[carbonyl-methoxypolyethylene glycol]-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE-PEG), N-[carbonyl-methoxypolyethylene glycol]-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG), and 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol. Polyethylene glycol derivatives such as N-[carbonyl-methoxypolyethylene glycol]-1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE-PEG) may be used.For example, N-[carbonyl-methoxypolyethylene glycol-2000]-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE-PEG2000), n-[carbonyl-methoxypolyethylene glycol-5000]-1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE-PEG5000), N-[carbonyl-methoxypolyethylene glycol-750]-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG750), N-[carbonyl-methoxypolyethylene glycol-2000]-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG2000) N-[carbonyl-methoxypolyethylene glycol-5000]-1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE-PEG5000), 1,2-dimiristoyl-rac-glycero-3-methoxypolyethylene glycol-750 (DMG-PEG750), 1,2-dimiristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000), 1,2-dimiristoyl-rac-glycero-3-methoxypolyethylene glycol-5000 Polyethylene glycol derivatives such as (DMG-PEG5000), N-[carbonyl-methoxypolyethylene glycol-750]-1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE-PEG750), N-[carbonyl-methoxypolyethylene glycol-2000]-1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE-PEG2000), and N-[carbonyl-methoxypolyethylene glycol-5000]-1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE-PEG5000) can also be used, but polyalkylene glycol-modified lipids are not limited to these.

[0056] The lipid nanoparticles of the present disclosure contain a targeting polyalkylene glycol-modified lipid as a constituent lipid. In the present disclosure, the "targeting polyalkylene glycol-modified lipid" refers to a polyalkylene glycol-modified lipid to which a target binding site is linked. In one embodiment, the target binding site is linked to the polyalkylene glycol, preferably linked to the polyalkylene glycol moiety of the polyalkylene glycol-modified lipid via a linker. In the present disclosure, "linked" means linked by a covalent bond. The ratio of the targeting polyalkylene glycol-modified lipid to the total lipid amount constituting the lipid nanoparticles according to the present invention is not particularly limited as long as it does not impair the gene expression activity when the lipid nanoparticles according to the present invention are used as a gene carrier.

[0057] 5. Linker In a preferred embodiment of the present invention, the target binding site is linked to the polyalkylene glycol of the targeting polyalkylene glycol-modified lipid via a linker. In one embodiment of the present invention, the linker refers to a group that links the target binding site and the polyalkylene glycol. The linker includes or consists of, for example, a peptide. The linker includes or consists of, for example, a peptide of 1 to 50 mers, 5 to 45 mers, 5 to 35 mers, 5 to 30 mers, 5 to 25 mers, 10 to 25 mers. In a preferred embodiment of the present invention, the linker is (Ser-Ser-Ser-Gly) m (SEQ ID NO: 1) [where m is an integer of 1 to 5], (Glu-Ala-Ala-Ala-Lys) n (SEQ ID NO: 2) [where n is an integer of 1 to 4], (Ala-Pro) ｐ [where p is an integer of 1 to 8], (His) ｑ [where q is an integer of 1 to 10], and includes at least one of them.

[0058] In a preferred embodiment of the present invention, the linker is (OCH ２ CH ２ ) ｒ [where r is an integer of 1 to 10].

[0059] In a preferred embodiment of the present invention, the linker has the following formula: The compound includes the site indicated by [wherein the formula, the left arrow indicates linkage with the peptide, the right arrow indicates linkage with the polyalkylene glycol, X is N or O, and r is an integer from 1 to 15].

[0060] In a preferred embodiment of the present invention, the linker is represented as -Z1-Z2-, where Z1 is linked to the target binding site, Z2 is linked to the polyalkylene glycol, and Z1 is It is represented as, and Z2 is, [In the formula, the left arrow indicates linkage to the adjacent Lys side chain amino group, the right arrow indicates linkage to the polyalkylene glycol, X is N or O, and r is an integer from 1 to 15]. In a preferred embodiment of the present invention, the linker is represented as -Z1-Z2-, where Z1 is linked to the target binding site, Z2 is linked to the polyalkylene glycol, and Z1 is It is represented as, and Z2 is, [In the formula, the left arrow indicates a linkage to the adjacent Lys side chain amino group, the right arrow indicates a linkage to the polyalkylene glycol, X is N or O, and r is an integer from 1 to 15.]

[0061] In a preferred embodiment of the present invention, the linker is represented as -Z1-Z2-, where Z1 is linked to the target site, Z2 is linked to the polyalkylene glycol, and Z1 is as follows: Z2 is one of the polypeptides shown, and Z2 is [In the formula, the left arrow indicates a linkage to the adjacent Cys side chain SH group, the right arrow indicates a linkage to the polyalkylene glycol, and X is N or O].

[0062] In a preferred embodiment of the present invention, the linker is represented as -Z1-Z2-, where Z1 is linked to the target binding site, Z2 is linked to the polyalkylene glycol, and Z1 is as follows: Z2 is one of the polypeptides shown, and Z2 is [In the formula, the left arrow indicates a linkage to the adjacent Cys side chain SH group, the right arrow indicates a linkage to the polyalkylene glycol, and X is N or O].

[0063] In this disclosure, the terms “polypeptide,” “peptide,” and “protein” are used interchangeably to refer to polymers of amino acid residues. These terms may include natural amino acid polymers and non-natural amino acid polymers in which one or more amino acid residues are artificial chemical analogs of corresponding natural amino acids.

[0064] The lipid nanoparticles according to the present invention contain 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), a neutral phospholipid, as a constituent lipid.

[0065] The lipid nanoparticles according to the present invention contain sterols or sterol derivatives as constituent lipids. Examples of sterols or sterol derivatives include animal-derived sterols such as cholesterol, cholesterol succinate, lanosterol, dihydrolanosterol, desmosterol, and dihydrocholesterol; plant-derived sterols (phytosterols) such as stigmasterol, sitosterol, β-sitosterol, campesterol, and brassicasterol; and microbial-derived sterols such as thymosterol and ergosterol. Preferably, the lipid nanoparticles according to the present invention contain cholesterol.

[0066] 6. Non-targeted polyalkylene glycol-modified lipids The lipid nanoparticles according to the present invention include non-targeted polyalkylene glycol-modified lipids as constituent lipids. In this disclosure, "non-targeted polyalkylene glycol-modified lipids" refers to polyalkylene glycol-modified lipids in which the target binding site is not linked. In one embodiment, the non-targeted polyalkylene glycol-modified lipids include polyalkylene glycol-modified lipids in which polyalkylene glycol is modified with a reactive group. In one embodiment, the non-targeted polyalkylene glycol-modified lipids include polyalkylene glycol-modified lipids in which the non-targeting site is linked to the polyalkylene glycol site. Although not particularly limited, lipids formed by the reaction of polyalkylene glycol modification, in which polyalkylene glycol is modified with a reactive group (e.g., maleimide), with a non-targeting molecule (e.g., L-Cysteine ​​when maleimide is the reactive group), are included in polyalkylene glycol-modified lipids in which the non-targeting site is linked to the polyalkylene glycol site. In one embodiment, the untargeted polyalkylene glycol-modified lipid includes a polyalkylene glycol-modified lipid in which the polyalkylene glycol is unmodified. In one embodiment, the untargeted polyalkylene glycol-modified lipid includes at least one of a polyalkylene glycol-modified lipid in which the polyalkylene glycol is modified with a reactive group, a polyalkylene glycol-modified lipid in which the untargeted site is linked to the polyalkylene glycol site, and a polyalkylene glycol-modified lipid in which the polyalkylene glycol is unmodified. The lipid portions of these polyalkylene glycol-modified lipids may be the same or different. The lipid portion of the untargeted polyalkylene glycol-modified lipid may be the same or different from the lipid portion of the targeted polyalkylene glycol-modified lipid.

[0067] 7. Reactive Groups In a preferred embodiment of the present invention, the untargeted polyalkylene glycol-modified lipid comprises a polyalkylene glycol-modified lipid in which the polyalkylene glycol is modified with a reactive group, and a polyalkylene glycol-modified lipid in which the polyalkylene glycol is unmodified. Reactive groups collectively refer to groups involved in the coupling reaction of two molecules, such as Michael addition reactions and click chemistry reactions. Examples of Michael addition reactions include, but are not limited to, nucleophilic addition reactions between a thiol group and maleimide. Examples of click chemistry reactions include, but are not limited to, [3+2] cycloaddition, thiol-ene reactions, Diels-Alder reactions, inverse electron-demand Diels-Alder reactions, and [4+1] cycloaddition. The reactive group preferably includes a group selected from the group consisting of acetylene, transcyclooctene, cyclooctin, diarylcyclooctin, oxime, ketone, aldehyde, thiol, free cysteine, amine, maleimide, NHS (N-hydroxysuccinimide), NHS ester (N-hydroxysuccinimide ester), isocyanate, isothiocyanate, methyl ester phosphine, norbornene, tetrazine, methylcyclopropene, azetine, cyanide, azide, and dibenzocyclooctin. The reactive group most preferably includes maleimide. In one embodiment of the present invention, the polyalkylene glycol-modified lipid, in which polyalkylene glycol is modified with a reactive group, includes DSPE-PEG. In one embodiment, the polyalkylene glycol-modified lipid, in which polyalkylene glycol is modified with a reactive group, includes DSPE-PEG, in which polyethylene glycol is modified with maleimide. In one embodiment of the present invention, the polyalkylene glycol-modified lipid, in which polyalkylene glycol is unmodified, includes DMG-PEG.

[0068] 8. Proportion of each constituent lipid in lipid nanoparticles In the lipid nanoparticles of the present invention, the amount of cationic lipids is 35.0 to 55.0 mol% of the total lipid amount of the lipid nanoparticles. For example, the amount of cationic lipids is 35.0 mol% or more, 35.5 mol% or more, 36.0 mol% or more, 36.5 mol% or more, 37.0 mol% or more, 37.5 mol% or more, 38.0 mol% or more, 38.5 mol% or more, 39.0 mol% or more, 39.5 mol% or more, 40.0 mol% or more, 40.5 mol% or more, 41.0 mol% or more, 41.5 mol% or more, 42.0 mol% or more, 42.5 mol% or more, 43.0 mol% or more, 43.5 mol% or more, relative to the total lipid amount of the lipid nanoparticles. Above, 44.0 mol% or more, 44.5 mol% or more, 45.0 mol% or more, 45.5 mol% or more, 46.0 mol% or more, 46.5 mol% or more, 47.0 mol% or more, 47.5 mol% or more, 48.0 mol% or more, 48.5 mol% or more, 49.0 mol% or more, 49.5 mol% or more, 50.0 mol% or more, 50.5 mol% or more, 51.0 mol% or more, 51.5 mol% or more, 52.0 mol% or more, 52.5 mol% or more, 53.0 mol% or more, 53.5 mol% or more, 54.0 m ol% or more, or 54.5 mol% or more, and 55.0 mol% or less, 54.5 mol% or less, 54.0 mol% or less, 53.5 mol% or less, 53.0 mol% or less, 52.5 mol% or less, 52.0 mol% or less, 51.5 mol% or less, 51.0 mol% or less, 50.5 mol% or less, 50.0 mol% or less, 49.5 mol% or less, 49.0 mol% or less, 48.5 mol% or less, 48.0 mol% or less, 47.5 mol% or less, 47.0 mol% or less, 46.5 mol% or less, 46.0 mol% or less, 45.5 mol% or less, 45.0 mol% or less, 44.5 mol% or less, 44.0 mol% or less, 43.5 mol% or less, 43.0 mol% or less, 42.5 mol% or less, 42.0 mol% or less, 41.5 mol% or less, 41.0 mol % or less, 40.5 mol% or less, 40.0 mol% or less, 39.5 mol% or less, 39.0 mol% or less, 38.5 mol% or less, 38.0 mol% or less, 37.5 mol% or less, 37.0 mol% or less, 36.5 mol% or less, 36.0 mol% or less,Or 35.5 mol% or less. Preferably, the amount of cationic lipid is 35.0 to 40.0 mol%, 35.0 to 40.5 mol%, 35.0 to 41.0 mol%, 35.0 to 41.5 mol%, 35.0 to 42.0 mol%, 35.0 to 42.5 mol%, 35.0 to 43.0 mol%, 35.0 to 43.5 mol%, 35.0 to 44.0 mol%, 35.0 to 44.5 mol%, 35.0 to 45.0 mol%, 35.0 to 45.5 mol%, 35.0 to 46.0 mol%, 35.0 to 46.5 mol%, 35.0 to 47.0 mol%, 35.0 ~47.5mol%, 35.0~48.0mol%, 35.0~48.5mol%, 35.0~49.0mol%, 35.0~49.5 mol%, 35.0-50.0 mol%, 35.0-50.5 mol%, 35.0-51.0 mol%, 35.0-51.5 mol%, 3 5.0-52.0 mol%, 35.0-52.5 mol%, 35.0-53.0 mol%, 35.0-53.5 mol%, 35.0-5 4.0 mol%, 35.0-54.5 mol%, 35.5-40.0 mol%, 35.5-40.5 mol%, 35.5-41.0 mol %, 35.5-41.5 mol%, 35.5-42.0 mol%, 35.5-42.5 mol%, 35.5-43.0 mol%, 35. 5-43.5 mol%, 35.5-44.0 mol%, 35.5-44.5 mol%, 35.5-45.0 mol%, 35.5-45.5 mol%, 35.5-46.0 mol%, 35.5-46.5 mol%, 35.5-47.0 mol%, 35.5-47.5 mol%, 35.5-48.0 mol%, 35.5-48.5 mol%, 35.5-49.0 mol%, 35.5-49.5 mol%, 35.5-5 0.0 mol%, 35.5-50.5 mol%, 35.5-51.0 mol%, 35.5-51.5 mol%, 35.5-52.0 mol l%, 35.5-52.5 mol%, 35.5-53.0 mol%, 35.5-53.5 mol%, 35.5-54.0 mol%, 35. 5-54.5 mol%, 35.5-55.0 mol%, 36.0-40.0 mol%, 36.0-40.5 mol%, 36.0-41. 0 mol%, 36.0-41.5 mol%, 36.0-42.0 mol%, 36.0-42.5 mol%, 36.0-43.0 mol%,36.0~43.5mol%、36.0~44.0mol%、36.0~44.5mol%、36.0~45.0mol%、36.0~45.5mol%、36.0~46.0mol%、36.0~46.5mol%、36.0~47.0mol%、36.0~47.5mol%、36.0~48.0mol%、36.0~48.5mol%、36.0~49.0mol%、36.0~49.5mol%、36.0~50.0mol%、36.0~50.5mol%、36.0~51.0mol%、36.0~51.5mol%、36.0~52.0mol%、36.0~52.5mol%、36.0~53.0mol%、36.0~53.5mol%、36.0~54.0mol%、36.0~54.5mol%、36.0~55.0mol%、36.5~40.0mol%、36.5~40.5mol%、36.5~41.0mol%、36.5~41.5mol%、36.5~42.0mol%、36.5~42.5mol%、36.5~43.0mol%、36.5~43.5mol%、36.5~44.0mol%、36.5~44.5mol%、36.5~45.0mol%、36.5~45.5mol%、36.5~46.0mol%、36.5~46.5mol%、36.5~47.0mol%、36.5~47.5mol%、36.5~48.0mol%、36.5~48.5mol%、36.5~49.0mol%、36.5~49.5mol%、36.5~50.0mol%、36.5~50.5mol%、36.5~51.0mol%、36.5~51.5mol%、36.5~52.0mol%、36.5~52.5mol%、36.5~53.0mol%、36.5~53.5mol%、36.5~54.0mol%、36.5~54.5mol%、36.5~55.0mol%、37.0~40.0mol%、37.0~40.5mol%、37.0~41.0mol%、37.0~41.5mol%、37.0~42.0mol%、37.0~42.5mol%、37.0~43.0mol%、37.0~43.5mol%、37.0~44.0mol%、37.0~44.5mol%、37.0~45.0mol%、37.0~45.5mol%、37.0~46.0mol%、37.0~46.5mol%、37.0~47.0mol%、37.0~47.5mol%、37.0~48.0mol%、37.0~48.5mol%、37.0~49.0mol%、37.0~49.5mol%、37.0~50.0mol%、37.0~50.5mol%、37.0~51.0mol%、37.0~51.5mol%、37.0~52.0mol%、37.0~52.5mol%、37.0~53.0mol%、37.0~53.5mol%、37.0~54.0mol%、37.0~54.5mol%、37.0~55.0mol%、37.5~40.0mol%、37.5~40.5mol%、37.5~41.0mol%、37.5~41.5mol%、37.5~42.0mol%、37.5~42.5mol%、37.5~43.0mol%、37.5~43.5mol%、37.5~44.0mol%、37.5~44.5mol%、37.5~45.0mol%、37.5~45.5mol%、37.5~46.0mol%、37.5~46.5mol%、37.5~47.0mol%、37.5~47.5mol%、37.5~48.0mol%、37.5~48.5mol%、37.5~49.0mol%、37.5~49.5mol%、37.5~50.0mol%、37.5~50.5mol%、37.5~51.0mol%、37.5~51.5mol%、37.5~52.0mol%、37.5~52.5mol%、37.5~53.0mol%、37.5~53.5mol%、37.5~54.0mol%、37.5~54.5mol%、37.5~55.0mol%、38.0~40.0mol%、38.0~40.5mol%、38.0~41.0mol%、38.0~41.5mol%、38.0~42.0mol%、38.0~42.5mol%、38.0~43.0mol%、38.0~43.5mol%、38.0~44.0mol%、38.0~44.5mol%、38.0~45.0mol%、38.0~45.5mol%、38.0~46.0mol%、38.0~46.5mol%、38.0~47.0mol%、38.0~47.5mol%、38.0~48.0mol%、38.0~48.5mol%、38.0~49.0mol%、38.0~49.5mol%、38.0~50.0mol%、38.0~50.5mol%、38.0~51.0mol%、38.0~51.5mol%、38.0~52.0mol%、38.0~52.5mol%、38.0~53.0mol%、38.0~53.5mol%、38.0~54.0mol%、38.0~54.5mol%、38.0~55.0mol%、38.5~40.0mol%、38.5~40.5mol%、38.5~41.0mol%、38.5~41.5mol%、38.5~42.0mol%、38.5~42.5mol%、38.5~43.0mol%、38.5~43.5mol%、38.5~44.0mol%、38.5~44.5mol%、38.5~45.0mol%、38.5~45.5mol%、38.5~46.0mol%、38.5~46.5mol%、38.5~47.0mol%、38.5~47.5mol%、38.5~48.0mol%、38.5~48.5mol%、38.5~49.0mol%、38.5~49.5mol%、38.5~50.0mol%、38.5~50.5mol%、38.5~51.0mol%、38.5~51.5mol%、38.5~52.0mol%、38.5~52.5mol%、38.5~53.0mol%、38.5~53.5mol%、38.5~54.0mol%、38.5~54.5mol%、38.5~55.0mol%、39.0~40.0mol%、39.0~40.5mol%、39.0~41.0mol%、39.0~41.5mol%、39.0~42.0mol%、39.0~42.5mol%、39.0~43.0mol%、39.0~43.5mol%、39.0~44.0mol%、39.0~44.5mol%、39.0~45.0mol%、39.0~45.5mol%、39.0~46.0mol%、39.0~46.5mol%、39.0~47.0mol%、39.0~47.5mol%、39.0~48.0mol%、39.0~48.5mol%、39.0~49.0mol%、39.0~49.5mol%、39.0~50.0mol%、39.0~50.5mol%、39.0~51.0mol%、39.0~51.5mol%、39.0~52.0mol%、39.0~52.5mol%、39.0~53.0mol%、39.0~53.5mol%、39.0~54.0mol%、39.0~54.5mol%、39.0~55.0mol%、39.5~40.0mol%、39.5~40.5mol%、39.5~41.0mol%、39.5~41.5mol%、39.5~42.0mol%、39.5~42.5mol%、39.5~43.0mol%、39.5~43.5mol%、39.5~44.0mol%、39.5~44.5mol%、39.5~45.0mol%、39.5~45.5mol%、39.5~46.0mol%、39.5~46.5mol%、39.5~47.0mol%、39.5~4 7.5mol%、39.5~48.0mol%、39.5~48.5mol%、39.5~49.0mol%、39.5~49.5mol%、39.5~50.0mol%、39.5~50.5mol%、39.5~51.0mol%、39.5~51.5mol%、39.5~52.0mol%、39.5~52.5mol%、39.5~53.0mol%、39.5~53.5mol%、39.5~54.0mol%、39.5~54.5mol%、39.5~55.0mol%、40.0~40.5mol%、40.0~41.0mol%、40.0~41.5mol%、40.0~42.0mol%、40.0~42.5mol%、40.0~43.0mol%、40.0~43.5mol%、40.0~44.0mol%、40.0~44.5mol%、40.0~45.0mol%、40.0~45.5mol%、40.0~46.0mol%、40.0~46.5mol%、40.0~47.0mol%、40.0~47.5mol%、40.0~48.0mol%、40.0~48.5mol%、40.0~49.0mol%、40.0~49.5mol%、40.0~50.0mol%、40.0~50.5mol%、40.0~51.0mol%、40.0~51.5mol%、40.0~52.0mol%、40.0~52.5mol%、40.0~53.0mol%、40.0~53.5mol%、40.0~54.0mol%、40.0~54.5mol%、40.0~55.0mol%、40.5~50.0mol%、40.5~50.5mol%、40.5~51.0mol%、40.5~51.5mol%、40.5~52.0mol%、40.5~52.5mol%、40.5~53.0mol%、40.5~53.5mol%、40.5~54.0mol%、40.5~54.5mol%、40.5~55.0mol%、41.0~50.0mol%、41.0~50.5mol%、41.0~51.0mol%、41.0~51.5mol%、41.0~52.0mol%、41.0~52.5mol%、41.0~53.0mol%、41.0~53.5mol%、41.0~54.0mol%、41.0~54.5mol%、41.0~55.0mol%、41.5~50.0mol%、41.5~50.5mol%、41.5~51.0mol%、41.5~51.5mol%、41.5~52.0mol%、41.5~52.5mol%、41.5~53.0mol%、41.5~53.5mol%、41.5~54.0mol%、41.5~54.5mol%、41.5~55.0mol%、42.0~50.0mol%、42.0~50.5mol%、42.0~51.0mol%、42.0~51.5mol%、42.0~52.0mol%、42.0~52.5mol%、42.0~53.0mol%、42.0~53.5mol%、42.0~54.0mol%、42.0~54.5mol%、42.0~55.0mol%、42.5~50.0mol%、42.5~50.5mol%、42.5~51.0mol%、42.5~51.5mol%、42.5~52.0mol%、42.5~52.5mol%、42.5~53.0mol%、42.5~53.5mol%、42.5~54.0mol%、42.5~54.5mol%、42.5~55.0mol%、43.0~50.0mol%、43.0~50.5mol%、43.0~51.0mol%、43.0~51.5mol%、43.0~52.0mol%、43.0~52.5mol%、43.0~53.0mol%、43.0~53.5mol%、43.0~54.0mol%、43.0~54.5mol%、43.0~55.0mol%、43.5~50.0mol%、43.5~50.5mol%、43.5~51.0mol%、43.5~51.5mol%、43.5~52.0mol%、43.5~52.5mol%、43.5~53.0mol%、43.5~53.5mol%、43.5~54.0mol%、43.5~54.5mol%、43.5~55.0mol%、44.0~50.0mol%、44.0~50.5mol%、44.0~51.0mol%、44.0~51.5mol%、44.0~52.0mol%、44.0~52.5mol%、44.0~53.0mol%、44.0~53.5mol%、44.0~54.0mol%、44.0~54.5mol%、44.0~55.0mol%、44.5~50.0mol%、44.5~50.5mol%、44.5~51.0mol%、44.5~51.5mol%、44.5~52.0mol%、44.5~52.5mol%、44.5~53.0mol%、44.5~53.5mol%、44.5~54.0mol%、44.5~54.5mol%、44.5~55.0mol%、45.0~50.0mol%、45.0~50.5mol%、45.0~51.0mol%、45.0~51.5mol%、45.0~52.0mol%、45.0~52.5mol%、45.0~53.0mol%、45.0~53.5mol%、45.0~54.0mol%、45.0~54.5mol%、45.0~55.0mol%、45.5~50.0mol%、45.5~50.5mol%、45.5~51.0mol%、45.5~51.5mol%、45.5~52.0mol%、45.5~52.5mol%、45.5~53.0mol%、45.5~53.5mol%、45.5~54.0mol%、45.5~54.5mol%、45.5~55.0mol%、46.0~50.0mol%、46.0~50.5mol%、46.0~51.0mol%、46.0~51.5mol%、46.0~52.0mol%、46.0~52.5mol%、46.0~53.0mol%、46.0~53.5mol%、46.0~54.0mol%、46.0~54.5mol%、46.0~55.0mol%、46.5~50.0mol%、46.5~50.5mol%、46.5~51.0mol%、46.5~51.5mol%、46.5~52.0mol%、46.5~52.5mol%、46.5~53.0mol%、46.5~53.5mol%、46.5~54.0mol%、46.5~54.5mol%、46.5~55.0mol%、47.0~50.0mol%、47.0~50.5mol%、47.0~51.0mol%、47.0~51.5mol%、47.0~52.0mol%、47.0~52.5mol%、47.0~53.0mol%、47.0~53.5mol%、47.0~54.0mol%、47.0~54.5mol%、47.0~55.0mol%、47.5~50.0mol%、47.5-50.5 mol%, 47.5-51.0 mol%, 47.5-51.5 mol%, 47.5-52.0 mol%, 47.5-52.5 mol%, 47.5-53.0 mol%, 47.5-53.5 mol%, 47.5-54.0 mol%, 47.5-54.5 mol%, 47.5-55.0 mol%, 48.0-50.0 mol%, 48.0-50.5 mol%, 48.0-51.0 mol%, 48.0-51.5 mol%, 48.0-52.0 mol%, 48.0-52.5 mol%, 48.0-53.0 mol%, 48.0-53.5 mol%, 48.0-54.0 mol%, 48.0-54.5 mol%, 48.0-55.0 mol%, 48.5-50.0 mol%, 48.5-50.5 mol%, 48.5-51.0 mol%, 48.5-51.5 mol%, 48.5-52.0 mol%, 48.5-52.5 mol%, 48.5-53.0 mol%, 48.5-53.5 mol%, 48.5-54.0 mol%, 48.5-54.5 mol%, 48.5-55.0 mol%, 4 9.0-50.0 mol%, 49.0-50.5 mol%, 49.0-51.0 mol%, 49.0-51.5 mol%, 49.0-52.0 mol%, 49.0-52.5 mol%, 49.0-53.0 mol%, 49.0-53.5 mol%, 4 9.0-54.0 mol%, 49.0-54.5 mol%, 49.0-55.0 mol%, 49.5-50.0 mol%, 49.5-50.5 mol%, 49.5-51.0 mol%, 49.5-51.5 mol%, 49.5-52.0 mol%, 49 The molal content ranges are 5-52.5 mol%, 49.5-53.0 mol%, 49.5-53.5 mol%, 49.5-54.0 mol%, 49.5-54.5 mol%, 49.5-55.0 mol%, 50.0-50.5 mol%, 50.0-51.0 mol%, 50.0-51.5 mol%, 50.0-52.0 mol%, 50.0-52.5 mol%, 50.0-53.0 mol%, 50.0-53.5 mol%, 50.0-54.0 mol%, 50.0-54.5 mol%, and 50.0-55.0 mol%.

[0069] The amount of sterol or sterol derivative is 25.0 to 40.0 mol% relative to the total lipid content of the lipid nanoparticles. For example, the amount of sterol or sterol derivative is 25.0 mol% or more, 25.5 mol% or more, 26.0 mol% or more, 26.5 mol% or more, 27.0 mol% or more, 27.5 mol% or more, 28.0 mol% or more, 28.5 mol% or more, 29.0 mol% or more, 29.5 mol% or more, 30.0 mol% or more, 30.5 mol% or more, 31.0 mol% or more, relative to the total lipid content of the lipid nanoparticles. mol% or more, 31.5 mol% or more, 32.0 mol% or more, 32.5 mol% or more, 33.0 mol% or more, 33.5 mol% or more, 34.0 mol% or more, 34.5 mol% or more, 35.0 mol% or more, 35.5 mol% or more, 36.0 mol% or more, 36.5 mol% or more, 37.0 mol% or more, 37.5 mol% or more, 38.0 mol% or more, 38.5 mol% or more, 39.0 mol 1% or more, 39.5 mol% or more, and 40.0 mol% or less, 39.5 mol% or less, 39.0 mol% or less, 38.5 mol% or less, 38.0 mol% or less, 37.5 mol% or less, 37.0 mol% or less, 36.5 mol% or less, 36.0 mol% or less, 35.5 mol% or less, 35.0 mol% or less, 34.5 mol% or less, 34.0 mol% or less, 33.5 mol% or less, 3 The percentages are 3.0 mol% or less, 32.5 mol% or less, 32.0 mol% or less, 31.5 mol% or less, 31.0 mol% or less, 30.5 mol% or less, 30.0 mol% or less, 29.5 mol% or less, 29.0 mol% or less, 28.5 mol% or less, 28.0 mol% or less, 27.5 mol% or less, 27.0 mol% or less, 26.5 mol% or less, 26.0 mol% or less, and 25.5 mol% or less. Preferably, the amount of sterol or sterol derivative is 25.0 to 28.5 mol%, 25.0 to 29.0 mol%, 25.0 to 29.5 mol%, 25.0 to 30.0 mol%, 25.0 to 30.5 mol%, 25.0 to 31.0 mol%, 25.0 to 31.5 mol%, 25.0 to 32.0 mol%, 25.0 to 32.5 mol%, 25.0 to 33.0 mol%, 25.0 to 33.5 mol%, 25.0 to 34.0 mol%, 25.0 to 34.5 mol%, relative to the total lipid amount of the lipid nanoparticles.25.0~35.0mol%、25.0~35.5mol%、25.0~36.0mol%、25.0~36.5mol%、25.0~37.0mol%、25.0~37.5mol%、25.0~38.0mol%、25.0~38.5mol%、25.0~39.0mol%、25.0~39.5mol%、25.5~28.5mol%、25.5~29.0mol%、25.5~29.5mol%、25.5~30.0mol%、25.5~30.5mol%、25.5~31.0mol%、25.5~31.5mol%、25.5~32.0mol%、25.5~32.5mol%、25.5~33.0mol%、25.5~33.5mol%、25.5~34.0mol%、25.5~34.5mol%、25.5~35.0mol%、25.5~35.5mol%、25.5~36.0mol%、25.5~36.5mol%、25.5~37.0mol%、25.5~37.5mol%、25.5~38.0mol%、25.5~38.5mol%、25.5~39.0mol%、25.5~39.5mol%、25.5~40.0mol%、26.0~28.5mol%、26.0~29.0mol%、26.0~29.5mol%、26.0~30.0mol%、26.0~30.5mol%、26.0~31.0mol%、26.0~31.5mol%、26.0~32.0mol%、26.0~32.5mol%、26.0~33.0mol%、26.0~33.5mol%、26.0~34.0mol%、26.0~34.5mol%、26.0~35.0mol%、26.0~35.5mol%、26.0~36.0mol%、26.0~36.5mol%、26.0~37.0mol%、26.0~37.5mol%、26.0~38.0mol%、26.0~38.5mol%、26.0~39.0mol%、26.0~39.5mol%、26.0~40.0mol%、26.5~28.5mol%、26.5~29.0mol%、26.5~29.5mol%、26.5~30.0mol%、26.5~30.5mol%、26.5~31.0mol%、26.5~31.5mol%、26.5~32.0mol%、26.5~32.5mol%、26.5~33.0mol%、26.5~33.5mol%、26.5~34.0mol%、26.5~34.5mol%、26.5~35.0mol%、26.5~35.5mol%、26.5~36.0mol%、26.5~36.5mol%、26.5~37.0mol%、26.5~37.5mol%、26.5~38.0mol%、26.5~38.5mol%、26.5~39.0mol%、26.5~39.5mol%、26.5~40.0mol%、27.0~28.5mol%、27.0~29.0mol%、27.0~29.5mol%、27.0~30.0mol%、27.0~30.5mol%、27.0~31.0mol%、27.0~31.5mol%、27.0~32.0mol%、27.0~32.5mol%、27.0~33.0mol%、27.0~33.5mol%、27.0~34.0mol%、27.0~34.5mol%、27.0~35.0mol%、27.0~35.5mol%、27.0~36.0mol%、27.0~36.5mol%、27.0~37.0mol%、27.0~37.5mol%、27.0~38.0mol%、27.0~38.5mol%、27.0~39.0mol%、27.0~39.5mol%、27.0~40.0mol%、27.5~28.5mol%、27.5~29.0mol%、27.5~29.5mol%、27.5~30.0mol%、27.5~30.5mol%、27.5~31.0mol%、27.5~31.5mol%、27.5~32.0mol%、27.5~32.5mol%、27.5~33.0mol%、27.5~33.5mol%、27.5~34.0mol%、27.5~34.5mol%、27.5~35.0mol%、27.5~35.5mol%、27.5~36.0mol%、27.5~36.5mol%、27.5~37.0mol%、27.5~37.5mol%、27.5~38.0mol%、27.5~38.5mol%、27.5~39.0mol%、27.5~39.5mol%、27.5~40.0mol%、28.0~28.5mol%、28.0~29.0mol%、28.0~29.5mol%、28.0~30.0mol%、28.0~30.5mol%、28.0~31.0mol%、28.0~31.5mol%、28.0~32.0mol%、28.0~32.5mol%、28.0~33.0mol%、28.0~33.5mol%、28.0~34.0mol%、28.0~34.5mol%、28.0~35.0mol%、28.0~35.5mol%、28.0~36.0mol%、28.0~36.5mol%、28.0~37.0mol%、28.0~37.5mol%、28.0~38.0mol%、28.0~38.5mol%、28.0~39.0mol%、28.0~39.5mol%、28.0~40.0mol%、28.5~29.0mol%、28.5~29.5mol%、28.5~30.0mol%、28.5~30.5mol%、28.5~31.0mol%、28.5~31.5mol%、28.5~32.0mol%、28.5~32.5mol%、28.5~33.0mol%、28.5~33.5mol%、28.5~34.0mol%、28.5~34.5mol%、28.5~35.0mol%、28.5~35.5mol%、28.5~36.0mol%、28.5~36.5mol%、28.5~37.0mol%、28.5~37.5mol%、28.5~38.0mol%、28.5~38.5mol%、28.5~39.0mol%、28.5~39.5mol%、28.5~40.0mol%、29.0~38.5mol%、29.0~39.0mol%、29.0~39.5mol%、29.0~40.0mol%、29.5~38.5mol%、29.5~39.0mol%、29.5~39.5mol%、29.5~40.0mol%、30.0~38.5mol%、30.0~39.0mol%、30.0~39.5mol%、30.0~40.0mol%、30.5~38.5mol%、30.5~39.0mol%、30.5~39.5mol%、30.5~40.0mol%、31.0~38.5mol%、31.0~39.0mol%、31.0~39.5mol%、31.0~40.0mol%、31.5~38.5mol%、31.5~39.0mol%、31.5~39.5mol%、31.5~40.0mol%、32.0~38.5mol%、32.0~39.0mol%、32.0~39.5mol%、32.0~40.0mol%、32.5~38.5mol%、32.5~39.0mol%、32.5~39.5mol%、32.5~40.0mol%、33.0~38.5mol%、33.0~39.0mol%、33.0~39.5mol%、33.0~40.0mol%、33.5-38.5 mol%, 33.5-39.0 mol%, 33.5-39.5 mol%, 33.5-40.0 mol%, 34.0-38.5 mol%, 34.0- 39.0 mol%, 34.0-39.5 mol%, 34.0-40.0 mol%, 34.5-38.5 mol%, 34.5-39.0 mol%, 34.5-39.5 mol l%, 34.5-40.0 mol%, 35.0-38.5 mol%, 35.0-39.0 mol%, 35.0-39.5 mol%, 35.0-40.0 mol%, 35 5-38.5 mol%, 35.5-39.0 mol%, 35.5-39.5 mol%, 36.0-38.5 mol%, 36.0-39. 0 mol%, 36.0-39.5 mol%, 36.0-40.0 mol%, 36.5-38.5 mol%, 36.5-39.0 mol%, 36.5-39.5 mol% , 36.5-40.0 mol%, 37.0-38.5 mol%, 37.0-39.0 mol%, 37.0-39.5 mol%, 37.0-40.0 mol%, 37.5- The concentrations are 38.5 mol%, 37.5–39.0 mol%, 37.5–39.5 mol%, 37.5–40.0 mol%, 38.0–38.5 mol%, 38.0–39.0 mol%, 38.0–39.5 mol%, 38.0–40.0 mol%, 38.5–39.0 mol%, 38.5–39.5 mol%, and 38.5–40.0 mol%.

[0070] The amount of DSPC is 15.0 to 35.0 mol% relative to the total lipid content of the lipid nanoparticles. For example, the amount of DSPC is 15.0 mol% or more, 15.5 mol% or more, 16.0 mol% or more, 16.5 mol% or more, 17.0 mol% or more, 17.5 mol% or more, 18.0 mol% or more, 18.5 mol% or more, 19.0 mol% or more, 19.5 mol% or more, 20.0 mol% or more, 20.5 mol% or more, 21.0 mol% or more, 21.5 mol% or more, 22.0 mol% or more, 22.5 mol% or more, 23.0 mol% or more, 23.5 mol% or more, 24. 0 mol% or more, 24.5 mol% or more, 25.0 mol% or more, 25.5 mol% or more, 26.0 mol% or more, 26.5 mol% or more, 27.0 mol% or more, 27.5 mol% or more, 28.0 mol% or more, 28.5 mol% or more, 29.0 mol% or more, 29.5 mol% or more, 30.0 mol% or more, 30.5 mol% or more, 31.0 mol% or more, 31.5 mol% or more, 32.0 mol% or more, 32.5 mol% or more, 33.0 mol% or more, 33.5 mol% or more, 34.0 mol% or more, or 3 4.5 mol% or more, and also 35.0 mol% or less, 34.5 mol% or less, 34.0 mol% or less, 33.5 mol% or less, 33.0 mol% or less, 32.5 mol% or less, 32.0 mol% or less, 31.5 mol% or less, 31.0 mol% or less, 30.5 mol% or less, 30.0 mol% or less, 29.5 mol% or less, 29.0 mol% or less, 28.5 mol% or less, 28.0 mol% or less, 27.5 mol% or less, 27.0 mol% or less, 26.5 mol% or less, 26.0 mol% or less, 25.5 m 1 mol% or less, 25.0 mol% or less, 24.5 mol% or less, 24.0 mol% or less, 23.5 mol% or less, 23.0 mol% or less, 22.5 mol% or less, 22.0 mol% or less, 21.5 mol% or less, 21.0 mol% or less, 20.5 mol% or less, 20.0 mol% or less, 19.5 mol% or less, 19.0 mol% or less, 18.5 mol% or less, 18.0 mol% or less, 17.5 mol% or less, 17.0 mol% or less, 16.5 mol% or less, 16.0 mol% or less, or 15.5 mol% or less. Preferably, the amount of DSPC isThe amounts of the aforementioned lipid nanoparticles are 15.0-20.0 mol%, 15.0-20.5 mol%, 15.0-21.0 mol%, 15.0-21.5 mol%, 15.0-22.0 mol%, 15.0-22.5 mol%, 15.0-23.0 mol%, 15.0-23.5 mol%, 15.0-24.0 mol%, 15.0-24.5 mol%, 15.0-25.0 mol%, 15.0-25.5 mol%, 15.0-26.0 mol%, 15.0-26.5 mol%, 15.0-27.0 mol%, 15.0-27.5 mol%, and 15.0-28. 0 mol%, 15.0 to 28.5 mol%, 15.0 to 29.0 mol%, 15.0 to 29.5 mol%, 15.0 to 30.0 mol%, 15.0-30.5 mol%, 15.0-31.0 mol%, 15.0-31.5 mol%, 15.0-32.0 mol%, 15.0-3 2.5 mol%, 15.0 to 33.0 mol%, 15.0 to 33.5 mol%, 15.0 to 34.0 mol%, 15.0 to 34.5 mol% %, 15.5-20.0 mol%, 15.5-20.5 mol%, 15.5-21.0 mol%, 15.5-21.5 mol%, 15.5-20.5 mol% 22.0 mol%, 15.5-22.5 mol%, 15.5-23.0 mol%, 15.5-23.5 mol%, 15.5-24.0 mol l%, 15.5-24.5 mol%, 15.5-25.0 mol%, 15.5-25.5 mol%, 15.5-26.0 mol%, 15. 5-26.5 mol%, 15.5-27.0 mol%, 15.5-27.5 mol%, 15.5-28.0 mol%, 15.5-28.5 mol%, 15.5-29.0 mol%, 15.5-29.5 mol%, 15.5-30.0 mol%, 15.5-30.5 mol%, 15 .. 5-31.0 mol%, 15.5-31.5 mol%, 15.5-32.0 mol%, 15.5-32.5 mol%, 15.5-33.0 mol%, 15.5-33.5 mol%, 15.5-34.0 mol%, 15.5-34.5 mol%, 15.5-35.0 mol%, 1 6.0-20.0 mol%, 16.0-20.5 mol%, 16.0-21.0 mol%, 16.0-21.5 mol%, 16.0-22 .0 mol%, 16.0-22.5 mol%, 16.0-23.0 mol%, 16.0-24.0 mol%,16.0~24.5mol%、16.0~25.0mol%、16.0~25.5mol%、16.0~26.0mol%、16.0~26.5mol%、16.0~27.0mol%、16.0~27.5mol%、16.0~28.0mol%、16.0~28.5mol%、16.0~29.0mol%、16.0~29.5mol%、16.0~30.0mol%、16.0~30.5mol%、16.0~31.0mol%、16.0~31.5mol%、16.0~32.0mol%、16.0~32.5mol%、16.0~33.0mol%、16.0~33.5mol%、16.0~34.0mol%、16.0~34.5mol%、16.0~35.0mol%、16.5~20.0mol%、16.5~20.5mol%、16.5~21.0mol%、16.5~21.5mol%、16.5~22.0mol%、16.5~22.5mol%、16.5~23.0mol%、16.5~23.5mol%、16.5~24.0mol%、16.5~24.5mol%、16.5~25.0mol%、16.5~25.5mol%、16.5~26.0mol%、16.5~26.5mol%、16.5~27.0mol%、16.5~27.5mol%、16.5~28.0mol%、16.5~28.5mol%、16.5~29.0mol%、16.5~29.5mol%、16.5~30.0mol%、16.5~30.5mol%、16.5~31.0mol%、16.5~31.5mol%、16.5~32.0mol%、16.5~32.5mol%、16.5~33.0mol%、16.5~33.5mol%、16.5~34.0mol%、16.5~34.5mol%、16.5~35.0mol%、17.0~20.0mol%、17.0~20.5mol%、17.0~21.0mol%、17.0~21.5mol%、17.0~22.0mol%、17.0~22.5mol%、17.0~23.0mol%、17.0~23.5mol%、17.0~24.0mol%、17.0~24.5mol%、17.0~25.0mol%、17.0~25.5mol%、17.0~26.0mol%、17.0~26.5mol%、17.0~27.0mol%、17.0~27.5mol%、17.0~28.0mol%、17.0~28.5mol%、17.0~29.0mol%、17.0~29.5mol%、17.0~30.0mol%、17.0~30.5mol%、17.0~31.0mol%、17.0~31.5mol%、17.0~32.0mol%、17.0~32.5mol%、17.0~33.0mol%、17.0~33.5mol%、17.0~34.0mol%、17.0~34.5mol%、17.0~35.0mol%、17.5~20.0mol%、17.5~20.5mol%、17.5~21.0mol%、17.5~21.5mol%、17.5~22.0mol%、17.5~22.5mol%、17.5~23.0mol%、17.5~23.5mol%、17.5~24.0mol%、17.5~24.5mol%、17.5~25.0mol%、17.5~25.5mol%、17.5~26.0mol%、17.5~26.5mol%、17.5~27.0mol%、17.5~27.5mol%、17.5~28.0mol%、17.5~28.5mol%、17.5~29.0mol%、17.5~29.5mol%、17.5~30.0mol%、17.5~30.5mol%、17.5~31.0mol%、17.5~31.5mol%、17.5~32.0mol%、17.5~32.5mol%、17.5~33.0mol%、17.5~33.5mol%、17.5~34.0mol%、17.5~34.5mol%、17.5~35.0mol%、18.0~20.0mol%、18.0~20.5mol%、18.0~21.0mol%、18.0~21.5mol%、18.0~22.0mol%、18.0~22.5mol%、18.0~23.0mol%、18.0~23.5mol%、18.0~24.0mol%、18.0~24.5mol%、18.0~25.0mol%、18.0~25.5mol%、18.0~26.0mol%、18.0~26.5mol%、18.0~27.0mol%、18.0~27.5mol%、18.0~28.0mol%、18.0~28.5mol%、18.0~29.0mol%、18.0~29.5mol%、18.0~30.0mol%、18.0~30.5mol%、18.0~31.0mol%、18.0~31.5mol%、18.0~32.0mol%、18.0~32.5mol%、18.0~33.0mol%、18.0~33.5mol%、18.0~34.0mol%、18.0~34.5mol%、18.0~35.0mol%、18.5~20.0mol%、18.5~20.5mol%、18.5~21.0mol%、18.5~21.5mol%、18.5~22.0mol%、18.5~22.5mol%、18.5~23.0mol%、18.5~23.5mol%、18.5~24.0mol%、18.5~24.5mol%、18.5~25.0mol%、18.5~25.5mol%、18.5~26.0mol%、18.5~26.5mol%、18.5~27.0mol%、18.5~27.5mol%、18.5~28.0mol%、18.5~28.5mol%、18.5~29.0mol%、18.5~29.5mol%、18.5~30.0mol%、18.5~30.5mol%、18.5~31.0mol%、18.5~31.5mol%、18.5~32.0mol%、18.5~32.5mol%、18.5~33.0mol%、18.5~33.5mol%、18.5~34.0mol%、18.5~34.5mol%、18.5~35.0mol%、19.0~20.0mol%、19.0~20.5mol%、19.0~21.0mol%、19.0~21.5mol%、19.0~22.0mol%、19.0~22.5mol%、19.0~23.0mol%、19.0~23.5mol%、19.0~24.0mol%、19.0~24.5mol%、19.0~25.0mol%、19.0~25.5mol%、19.0~26.0mol%、19.0~26.5mol%、19.0~27.0mol%、19.0~27.5mol%、19.0~28.0mol%、19.0~28.5mol%、19.0~29.0mol%、19.0~29.5mol%、19.0~30.0mol%、19.0~30.5mol%、19.0~31.0mol%、19.0~31.5mol%、19.0~32.0mol%、19.0~32.5mol%、19.0~33.0mol%、19.0~33.5mol%、19.0~34.0mol%、19.0~34.5mol%、19.0~35.0mol%、19.5~20.0mol%、19.5~20.5mol%、19.5~21.0mol%、19.5~21.5mol%、19.5~22.0mol%、19.5~22.5mol%、19.5~23.0mol%、19.5~23.5mol%、19.5~24.0mol%、19.5~24.5mol%、19.5~25.0mol%、19.5~25.5mol%、19.5~26.0mol%、19.5~26.5mol%、19.5~27.0mol%、19.5~27.5mol%、19.5~28. 0mol%、19.5~28.5mol%、19.5~29.0mol%、19.5~29.5mol%、19.5~30.0mol%、19.5~30.5mol%、19.5~31.0mol%、19.5~31.5mol%、19.5~32.0mol%、19.5~32.5mol%、19.5~33.0mol%、19.5~33.5mol%、19.5~34.0mol%、19.5~34.5mol%、19.5~35.0mol%、20.0~20.0mol%、20.0~20.5mol%、20.0~21.0mol%、20.0~21.5mol%、20.0~22.0mol%、20.0~22.5mol%、20.0~23.0mol%、20.0~23.5mol%、20.0~24.0mol%、20.0~24.5mol%、20.0~25.0mol%、20.0~25.5mol%、20.0~26.0mol%、20.0~26.5mol%、20.0~27.0mol%、20.0~27.5mol%、20.0~28.0mol%、20.0~28.5mol%、20.0~29.0mol%、20.0~29.5mol%、20.0~30.0mol%、20.0~30.5mol%、20.0~31.0mol%、20.0~31.5mol%、20.0~32.0mol%、20.0~32.5mol%、20.0~33.0mol%、20.0~33.5mol%、20.0~34.0mol%、20.0~34.5mol%、20.0~35.0mol%、20.5~30.0mol%、20.5~30.5mol%、20.5~31.0mol%、20.5~31.5mol%、20.5~32.0mol%、20.5~32.5mol%、20.5~33.0mol%、20.5~33.5mol%、20.5~34.0mol%、20.5~34.5mol%、20.5~35.0mol%、21.0~30.0mol%、21.0~30.5mol%、21.0~31.0mol%、21.0~31.5mol%、21.0~32.0mol%、21.0~32.5mol%、21.0~33.0mol%、21.0~33.5mol%、21.0~34.0mol%、21.0~34.5mol%、21.0~35.0mol%、21.5~30.0mol%、21.5~30.5mol%、21.5~31.0mol%、21.5~31.5mol%、21.5~32.0mol%、21.5~32.5mol%、21.5~33.0mol%、21.5~33.5mol%、21.5~34.0mol%、21.5~34.5mol%、21.5~35.0mol%、22.0~30.0mol%、22.0~30.5mol%、22.0~31.0mol%、22.0~31.5mol%、22.0~32.0mol%、22.0~32.5mol%、22.0~33.0mol%、22.0~33.5mol%、22.0~34.0mol%、22.0~34.5mol%、22.0~35.0mol%、22.5~30.0mol%、22.5~30.5mol%、22.5~31.0mol%、22.5~31.5mol%、22.5~32.0mol%、22.5~32.5mol%、22.5~33.0mol%、22.5~33.5mol%、22.5~34.0mol%、22.5~34.5mol%、22.5~35.0mol%、23.0~30.0mol%、23.0~30.5mol%、23.0~31.0mol%、23.0~31.5mol%、23.0~32.0mol%、23.0~32.5mol%、23.0~33.0mol%、23.0~33.5mol%、23.0~34.0mol%、23.0~34.5mol%、23.0~35.0mol%、23.5~30.0mol%、23.5~30.5mol%、23.5~31.0mol%、23.5~31.5mol%、23.5~32.0mol%、23.5~32.5mol%、23.5~33.0mol%、23.5~33.5mol%、23.5~34.0mol%、23.5~34.5mol%、23.5~35.0mol%、24.0~30.0mol%、24.0~30.5mol%、24.0~31.0mol%、24.0~31.5mol%、24.0~32.0mol%、24.0~32.5mol%、24.0~33.0mol%、24.0~33.5mol%、24.0~34.0mol%、24.0~34.5mol%、24.0~35.0mol%、24.5~30.0mol%、24.5~30.5mol%、24.5~31.0mol%、24.5~31.5mol%、24.5~32.0mol%、24.5~32.5mol%、24.5~33.0mol%、24.5~33.5mol%、24.5~34.0mol%、24.5~34.5mol%、24.5~35.0mol%、25.0~30.0mol%、25.0~30.5mol%、25.0~31.0mol%、25.0~31.5mol%、25.0~32.0mol%、25.0~32.5mol%、25.0~33.0mol%、25.0~33.5mol%、25.0~34.0mol%、25.0~34.5mol%、25.0~35.0mol%、25.5~30.0mol%、25.5~30.5mol%、25.5~31.0mol%、25.5~31.5mol%、25.5~32.0mol%、25.5~32.5mol%、25.5~33.0mol%、25.5~33.5mol%、25.5~34.0mol%、25.5~34.5mol%、25.5~35.0mol%、26.0~30.0mol%、26.0~30.5mol%、26.0~31.0mol%、26.0~31.5mol%、26.0~32.0mol%、26.0~32.5mol%、26.0~33.0mol%、26.0~33.5mol%、26.0~34.0mol%、26.0~34.5mol%、26.0~35.0mol%、26.5~30.0mol%、26.5~30.5mol%、26.5~31.0mol%、26.5~31.5mol%、26.5~32.0mol%、26.5~32.5mol%、26.5~33.0mol%、26.5~33.5mol%、26.5~34.0mol%、26.5~34.5mol%、26.5~35.0mol%、27.0~30.0mol%、27.0~30.5mol%、27.0~31.0mol%、27.0~31.5mol%、27.0~32.0mol%、27.0~32.5mol%、27.0~33.0mol%、27.0~33.5mol%、27.0~34.0mol%、27.0~34.5mol%、27.0~35.0mol%、27.5~30.0mol%、27.5~30.5mol%、27.5-31.0 mol%, 27.5-31.5 mol%, 27.5-32.0 mol%, 27.5-32.5 mol%, 27.5-33.0 mol%, 27.5-33.5 mol%, 27.5-34.0 mol%, 27.5-34.5 mol %, 27.5-35.0 mol%, 28.0-30.0 mol%, 28.0-30.5 mol%, 28.0-31.0 mol%, 28.0-31.5 mol%, 28.0-32.0 mol%, 28.0-32.5 mol%, 28.0-33.0 mol l%, 28.0-33.5 mol%, 28.0-34.0 mol%, 28.0-34.5 mol%, 28.0-35.0 mol%, 28.5-30.0 mol%, 28.5-30.5 mol%, 28.5-31.0 mol%, 28.5-31.5 mol%, 28.5-32.0 mol%, 28.5-32.5 mol%, 28.5-33.0 mol%, 28.5-33.5 mol%, 28.5-34.0 mol%, 28.5-34.5 mol%, 28.5-35.0 mol%, 29.0-30. 0 mol%, 29.0-30.5 mol%, 29.0-31.0 mol%, 29.0-31.5 mol%, 29.0-32.0 mol%, 29.0-32.5 mol%, 29.0-33.0 mol%, 29.0-33.5 mol%, 29.0-3 4.0 mol%, 29.0-34.5 mol%, 29.0-35.0 mol%, 29.5-30.0 mol%, 29.5-30.5 mol%, 29.5-31.0 mol%, 29.5-31.5 mol%, 29.5-32.0 mol%, 29.5- The concentrations are 32.5 mol%, 29.5–33.0 mol%, 29.5–33.5 mol%, 29.5–34.0 mol%, 29.5–34.5 mol%, 29.5–35.0 mol%, 30.0–30.5 mol%, 30.0–31.0 mol%, 30.0–31.5 mol%, 30.0–32.0 mol%, 30.0–32.5 mol%, 30.0–33.0 mol%, 30.0–33.5 mol%, 30.0–34.0 mol%, 30.0–34.5 mol%, and 30.0–35.0 mol%.

[0071] In one embodiment, the total amount of polyalkylene glycol-modified lipids linked to a target binding site and polyalkylene glycol-modified lipids not linked to a target binding site is 1.0 to 2.2 mol% of the total lipid content of the lipid nanoparticles. For example, the total amount of polyalkylene glycol-modified lipids linked to a target binding site and polyalkylene glycol-modified lipids not linked to a target binding site is 1.0 mol%, 1.1 mol%, 1.2 mol%, 1.3 mol%, 1.4 mol%, 1.5 mol%, 1.6 mol%, 1.7 mol%, 1.8 mol%, 1.9 mol%, 2.0 mol%, 2.1 mol%, or 2.2 mol% of the total lipid content of the lipid nanoparticles. Preferably, the total amount of polyalkylene glycol-modified lipids linked to the target binding site and polyalkylene glycol-modified lipids not linked to the target binding site is 1.0-1.5 mol%, 1.0-1.6 mol%, 1.0-1.7 mol%, 1.0-1.8 mol%, 1.0-1.9 mol%, 1.0-2.0 mol%, and 1.0-2.1 mol% relative to the total lipid amount of the lipid nanoparticles. l%, 1.0 to 2.2 mol%, 1.1 to 1.5 mol%, 1.1 to 1.6 mol%, 1.1 to 1.7 mol%, 1.1 to 1.8 mol%, 1.1 to 1.9 mol%, 1.1 to 2.0 mol l%, 1.1-2.1 mol%, 1.1-2.2 mol%, 1.2-1.5 mol%, 1.2-1.6 mol%, 1.2-1.7 mol%, 1.2-1.8 mol%, 1.2-1.9 mol %, 1.2-2.0 mol%, 1.2-2.1 mol%, 1.2-2.2 mol%, 1.3-1.5 mol%, 1.3-1.6 mol%, 1.3-1.7 mol%, 1.3-1.8 mol %, 1.3-1.9 mol%, 1.3-2.0 mol%, 1.3-2.1 mol%, 1.3-2.2 mol%, 1.4-1.5 mol%, 1.4-1.6 mol%, 1.4-1.7 mol% The concentrations are 1.4-1.8 mol%, 1.4-1.9 mol%, 1.4-2.0 mol%, 1.4-2.1 mol%, 1.4-2.2 mol%, 1.5-1.6 mol%, 1.5-1.7 mol%, 1.5-1.8 mol%, 1.5-1.9 mol%, 1.5-2.0 mol%, 1.5-2.1 mol%, and 1.5-2.2 mol%, with a more preferred concentration of 1.0-1.8 mol%.

[0072] In one embodiment, the amount of polyalkylene glycol-modified lipid not linked to a target binding site is 0.50 mol% or more and less than 2.20 mol% relative to the total lipid content of the lipid nanoparticles. For example, the amount of polyalkylene glycol-modified lipid linked to a target binding site is 0.50 mol%, 0.55 mol%, 0.60 mol%, 0.65 mol%, 0.70 mol%, 0.75 mol%, 0.80 mol%, 0.85 mol%, 0.90 mol%, 0.95 mol%, 1.00 mol%, 1.05 mol%, 1.10 mol%, 1.15 mol%, 1.20 mol%, 1.25 mol%, and 1.3 mol% relative to the total lipid content of the lipid nanoparticles. The concentrations are 0 mol%, 1.35 mol%, 1.40 mol%, 1.45 mol%, 1.50 mol%, 1.55 mol%, 1.60 mol%, 1.65 mol%, 1.70 mol%, 1.75 mol%, 1.80 mol%, 1.85 mol%, 1.90 mol%, 1.95 mol%, 2.00 mol%, 2.05 mol%, 2.10 mol%, 2.15 mol%, 2.16 mol%, 2.17 mol%, 2.18 mol%, and 2.19 mol%.Preferably, the amount of polyalkylene glycol-modified lipid not linked to the target binding site is 0.55 mol% or more and less than 2.20 mol%, 0.60 mol% or more and less than 2.20 mol%, 0.65 mol% or more and less than 2.20 mol%, 0.70 mol% or more and less than 2.20 mol%, 0.75 mol% or more and less than 2.20 mol%, 0.80 mol% or more and less than 2.20 mol%, 0.85 mol% or more and less than 2.20 mol%, and 0.90 mol% or more and 2.20 mol% relative to the total lipid amount of the lipid nanoparticles. Less than 1%, 0.95 mol% or more and less than 2.20 mol%, 1.00 mol% or more and less than 2.20 mol%, 1.05 mol% or more and less than 2.20 mol%, 1.10 mol% or more and less than 2.20 mol%, 1.15 mol% or more and less than 2.20 mol%, 1.20 mol% or more and less than 2.20 mol%, 1.25 mol% or more and less than 2.20 mol%, 1.30 mol% or more and less than 2.20 mol%, 1.35 mol% or more and less than 2.20 mol%, 1.40 mol% or more and less than 2.20 mol%, 1.45 m 0.60 mol% to 1.50 mol%, 0.70 mol% to 1.50 mol%, 0.75 mol% to 1.50 mol%, 0.80 mol% to 1.50 mol%, 0.85 mol% to 1.50 mol%, 0.90 mol% to 1.50 mol%, 0.95 mol% to 1.50 mol% These are mol% or less, 1.00 mol% to 1.50 mol%, 1.05 mol% to 1.50 mol%, 1.10 mol% to 1.50 mol%, 1.15 mol% to 1.50 mol%, 1.20 mol% to 1.50 mol%, 1.25 mol% to 1.50 mol%, 1.30 mol% to 1.50 mol%, 1.35 mol% to 1.50 mol%, 1.40 mol% to 1.50 mol%, and 1.45 mol% to 1.50 mol.

[0073] In one embodiment, the amount of polyalkylene glycol-modified lipid linked to the target binding site is greater than 0 mol% and less than or equal to 1.00 mol% of the total lipid content of the lipid nanoparticles. For example, the amounts of polyalkylene glycol-modified lipids linked to the target binding site are 0.01 mol%, 0.02 mol%, 0.03 mol%, 0.04 mol%, 0.05 mol%, 0.10 mol%, 0.15 mol%, 0.20 mol%, 0.25 mol%, 0.30 mol%, 0.35 mol%, 0.40 mol%, 0.45 mol%, 0.50 mol%, 0.55 mol%, 0.60 mol%, 0.65 mol%, 0.70 mol%, 0.75 mol%, 0.80 mol%, 0.85 mol%, 0.90 mol%, 0.95 mol%, and 1.00 mol%, relative to the total lipid amount of the lipid nanoparticles. Preferably, the amount of polyalkylene glycol-modified lipid linked to the target binding site is greater than 0 mol% and 0.95 mol% or less, greater than 0 mol% and 0.90 mol% or less, greater than 0 mol% and 0.85 mol% or less, greater than 0 mol% and 0.80 mol% or less, greater than 0 mol% and 0.75 mol% or less, greater than 0 mol% and 0.70 mol% or less, greater than 0 mol% and 0.65 mol% or less, greater than 0 mol% and 0.60 mol% or less, greater than 0 mol% and 0.55 mol% or less, greater than 0 mol% and 0.50 mol% or less, and 0.10 m These ranges are ol% to 1.00 mol%, 0.10 mol% to 0.95 mol%, 0.10 mol% to 0.90 mol%, 0.10 mol% to 0.85 mol%, 0.10 mol% to 0.80 mol%, 0.10 mol% to 0.75 mol%, 0.10 mol% to 0.70 mol%, 0.10 mol% to 0.65 mol%, 0.10 mol% to 0.60 mol%, 0.10 mol% to 0.55 mol%, and 0.10 mol% to 0.50 mol.

[0074] In one embodiment, the amount of polyalkylene glycol-modified lipid linked to the target binding site is more than 0% and 60% or less, preferably more than 0% and 55% or less, more than 0% and 50% or less, more than 0% and 45% or less, more than 0% and 40% or less, more than 0% and 35% or less, more than 0% and 30% or less, more than 0% and 25% or less, more than 0% and 20% or less, more than 0% and 15% or less, more than 0% and 10% or less, 1% or more and 55% or less, 1% or more and 50% or less, 1% or more and 45% or less, 1% or more and 40% or less, 1% or more and 35% or less, 1% or more and 30% or less, 1% or more and 25% or less, and 1% or more and 20% or more. The following percentages apply: 1% to 15%, 1% to 10%, 3% to 55%, 3% to 50%, 3% to 45%, 3% to 40%, 3% to 35%, 3% to 30%, 3% to 25%, 3% to 20%, 3% to 15%, 3% to 10%, 5% to 55%, 5% to 50%, 5% to 45%, 5% to 40%, 5% to 35%, 5% to 30%, 5% to 25%, 5% to 20%, 5% to 15%, and 5% to 10%.

[0075] In one embodiment, the molar ratios of each constituent lipid in the lipid nanoparticles of the present invention (cationic lipid / sterol or sterol derivative / DSPC / polyalkylene glycol-modified lipid) are (35.0 / 28.0 / 35.0 / 2.0), (35.0 / 28.5 / 34.5 / 2.0), (35.0 / 28.5 / 35.0 / 1.5), (35.0 / 29.0 / 34.0 / 2.0), (35.0 / 29.0 / 34.5 / 1.5), (35.0 / 29.0 / 35.0 / 1.0), (35.0 / 29.5 / 33.5 / 2.0), (35.0 / 29.5 / 34.0 / 1.5), (35.0 / 29.5 / 34.5 / 1.0), (35.0 / 30.0 / 33.0 / 2.0), (35.0 / 30.0 / 33.5 / 1.5), (35.0 / 30.0 / 34.0 / 1.0), (35.0 / 30.5 / 32.5 / 2.0), (35.0 / 30.5 / 33.0 / 1.5), (35.0 / 30.5 / 33.5 / 1.0), (35.0 / 31.0 / 32.0 / 2.0), (35.0 / 31.0 / 32.5 / 1.5), (35.0 / 31.0 / 33.0 / 1.0), (35.0 / 31.5 / 31.5 / 2.0), (35.0 / 31.5 / 32.0 / 1.5), (35.0 / 31.5 / 32.5 / 1.0), (35.0 / 32.0 / 31.0 / 2.0), (35.0 / 32.0 / 31.5 / 1.5), (35.0 / 32.0 / 32.0 / 1.0), (35.0 / 32.5 / 30.5 / 2.0), (35.0 / 32.5 / 31.0 / 1.5), (35.0 / 32.5 / 31.5 / 1.0), (35.0 / 33.0 / 30.0 / 2.0), (35.0 / 33.0 / 30.5 / 1.5), (35.0 / 33.0 / 31.0 / 1.0), (35.0 / 33.5 / 29.5 / 2.0), (35.0 / 33.5 / 30.0 / 1.5), (35.0 / 33.5 / 30.5 / 1.0), (35.0 / 34.0 / 29.0 / 2.0), (35.0 / 34.0 / 29.5 / 1.5), (35.0 / 34.0 / 30.0 / 1.0), (35.0 / 34.5 / 28.5 / 2.0), (35.0 / 34.5 / 29.0 / 1.5), (35.0 / 34.5 / 29.5 / 1.0), (35.0 / 35.0 / 28.0 / 2.0), (35.0 / 35.0 / 28.5 / 1.5), (35.0 / 35.0 / 29.0 / 1.0), (35.0 / 35.5 / 27.5 / 2.0),（３５．０／３５．５／２８．０／１．５）、（３５．０／３５．５／２８．５／１．０）、（３５．０／３６．０／２７．０／２．０）、（３５．０／３６．０／２７．５／１．５）、（３５．０／３６．０／２８．０／１．０）、（３５．０／３６．５／２６．５／２．０）、（３５．０／３６．５／２７．０／１．５）、（３５．０／３６．５／２７．５／１．０）、（３５．０／３７．０／２６．０／２．０）、（３５．０／３７．０／２６．５／１．５）、（３５．０／３７．０／２７．０／１．０）、（３５．０／３７．５／２５．５／２．０）、（３５．０／３７．５／２６．０／１．５）、（３５．０／３７．５／２６．５／１．０）、（３５．０／３８．０／２５．０／２．０）、（３５．０／３８．０／２５．５／１．５）、（３５．０／３８．０／２６．０／１．０）、（３５．０／３８．５／２４．５／２．０）、（３５．０／３８．５／２５．０／１．５）、（３５．０／３８．５／２５．５／１．０）、（３５．０／３９．０／２４．０／２．０）、（３５．０／３９．０／２４．５／１．５）、（３５．０／３９．０／２５．０／１．０）、（３５．０／３９．５／２３．５／２．０）、（３５．０／３９．５／２４．０／１．５）、（３５．０／３９．５／２４．５／１．０）、（３５．０／４０．０／２３．０／２．０）、（３５．０／４０．０／２３．５／１．５）、（３５．０／４０．０／２４．０／１．０）、（３５．５／２７．５／３５．０／２．０）、（３５．５／２８．０／３４．５／２．０）、（３５．５／２８．０／３５．０／１．５）、（３５．５／２８．５／３４．０／２．０）、（３５．５／２８．５／３４．５／１．５）、（３５．５／２８．５／３５．０／１．０）、（３５．５／２９．０／３３．５／２．０）、（３５．５／２９．０／３４．０／１．５）、（３５．５／２９．０／３４．５／１．０）、（３５．５／２９．５／３３．０／２．０）、（３５．５／２９．５／３３．５／１．５）、（３５．５／２９．５／３４．０／１．０）、（３５．５／３０．０／３２．５／２．０）、（３５．５／３０．０／３３．０／１．５）、（３５．５／３０．０／３３．５／１．０）、（３５．５／３０．５／３２．０／２．０）、（３５．５／３０．５／３２．５／１．５）、（３５．５／３０．５／３３．０／１．０）、（３５．５／３１．０／３１．５／２．０）、（３５．５／３１．０／３２．０／１．５）、（３５．５／３１．０／３２．５／１．０）、（３５．５／３１．５／３１．０／２．０）、（３５．５／３１．５／３１．５／１．５）、（３５．５／３１．５／３２．０／１．０）、（３５．５／３２．０／３０．５／２．０）、（３５．５／３２．０／３１．０／１．５）、（３５．５／３２．０／３１．５／１．０）、（３５．５／３２．５／３０．０／２．０）、（３５．５／３２．５／３０．５／１．５）、（３５．５／３２．５／３１．０／１．０）、（３５．５／３３．０／２９．５／２．０）、（３５．５／３３．０／３０．０／１．５）、（３５．５／３３．０／３０．５／１．０）、（３５．５／３３．５／２９．０／２．０）、（３５．５／３３．５／２９．５／１．５）、（３５．５／３３．５／３０．０／１．０）、（３５．５／３４．０／２８．５／２．０）、（３５．５／３４．０／２９．０／１．５）、（３５．５／３４．０／２９．５／１．０）、（３５．５／３４．５／２８．０／２．０）、（３５．５／３４．５／２８．５／１．５）、（３５．５／３４．５／２９．０／１．０）、（３５．５／３５．０／２７．５／２．０）、（３５．５／３５．０／２８．０／１．５）、（３５．５／３５．０／２８．５／１．０）、（３５．５／３５．５／２７．０／２．０）、（３５．５／３５．５／２７．５／１．５）、（３５．５／３５．５／２８．０／１．０）、（３５．５／３６．０／２６．５／２．０）、（３５．５／３６．０／２７．０／１．５）、（３５．５／３６．０／２７．５／１．０）、（３５．５／３６．５／２６．０／２．０）、（３５．５／３６．５／２６．５／１．５）、（３５．５／３６．５／２７．０／１．０）、（３５．５／３７．０／２５．５／２．０）、（３５．５／３７．０／２６．０／１．５）、（３５．５／３７．０／２６．５／１．０）、（３５．５／３７．５／２５．０／２．０）、（３５．５／３７．５／２５．５／１．５）、（３５．５／３７．５／２６．０／１．０）、（３５．５／３８．０／２４．５／２．０）、（３５．５／３８．０／２５．０／１．５）、（３５．５／３８．０／２５．５／１．０）、（３５．５／３８．５／２４．０／２．０）、（３５．５／３８．５／２４．５／１．５）、（３５．５／３８．５／２５．０／１．０）、（３５．５／３９．０／２３．５／２．０）、（３５．５／３９．０／２４．０／１．５）、（３５．５／３９．０／２４．５／１．０）、（３５．５／３９．５／２３．０／２．０）、（３５．５／３９．５／２３．５／１．５）、（３５．５／３９．５／２４．０／１．０）、（３５．５／４０．０／２２．５／２．０）、（３５．５／４０．０／２３．０／１．５）、（３５．５／４０．０／２３．５／１．０）、（３６．０／２７．０／３５．０／２．０）、（３６．０／２７．５／３４．５／２．０）、（３６．０／２７．５／３５．０／１．５）、（３６．０／２８．０／３４．０／２．０）、（３６．０／２８．０／３４．５／１．５）、（３６．０／２８．０／３５．０／１．０）、（３６．０／２８．５／３３．５／２．０）、（３６．０／２８．５／３４．０／１．５）、（３６．０／２８．５／３４．５／１．０）、（３６．０／２９．０／３３．０／２．０）、（３６．０／２９．０／３３．５／１．５）、（３６．０／２９．０／３４．０／１．０）、（３６．０／２９．５／３２．５／２．０）、（３６．０／２９．５／３３．０／１．５）、（３６．０／２９．５／３３．５／１．０）、（３６．０／３０．０／３２．０／２．０）、（３６．０／３０．０／３２．５／１．５）、（３６．０／３０．０／３３．０／１．０）、（３６．０／３０．５／３１．５／２．０）、（３６．０／３０．５／３２．０／１．５）、（３６．０／３０．５／３２．５／１．０）、（３６．０／３１．０／３１．０／２．０）、（３６．０／３１．０／３１．５／１．５）、（３６．０／３１．０／３２．０／１．０）、（３６．０／３１．５／３０．５／２．０）、（３６．０／３１．５／３１．０／１．５）、（３６．０／３１．５／３１．５／１．０）、（３６．０／３２．０／３０．０／２．０）、（３６．０／３２．０／３０．５／１．５）、（３６．０／３２．０／３１．０／１．０）、（３６．０／３２．５／２９．５／２．０）、（３６．０／３２．５／３０．０／１．５）、（３６．０／３２．５／３０．５／１．０）、（３６．０／３３．０／２９．０／２．０）、（３６．０／３３．０／２９．５／１．５）、（３６．０／３３．０／３０．０／１．０）、（３６．０／３３．５／２８．５／２．０）、（３６．０／３３．５／２９．０／１．５）、（３６．０／３３．５／２９．５／１．０）、（３６．０／３４．０／２８．０／２．０）、（３６．０／３４．０／２８．５／１．５）、（３６．０／３４．０／２９．０／１．０）、（３６．０／３４．５／２７．５／２．０）、（３６．０／３４．５／２８．０／１．５）、（３６．０／３４．５／２８．５／１．０）、（３６．０／３５．０／２７．０／２．０）、（３６．０／３５．０／２７．５／１．５）、（３６．０／３５．０／２８．０／１．０）、（３６．０／３５．５／２６．５／２．０）、（３６．０／３５．５／２７．０／１．５）、（３６．０／３５．５／２７．５／１．０）、（３６．０／３６．０／２６．０／２．０）、（３６．０／３６．０／２６．５／１．５）、（３６．０／３６．０／２７．０／１．０）、（３６．０／３６．５／２５．５／２．０）、（３６．０／３６．５／２６．０／１．５）、（３６．０／３６．５／２６．５／１．０）、（３６．０／３７．０／２５．０／２．０）、（３６．０／３７．０／２５．５／１．５）、（３６．０／３７．０／２６．０／１．０）、（３６．０／３７．５／２４．５／２．０）、（３６．０／３７．５／２５．０／１．５）、（３６．０／３７．５／２５．５／１．０）、（３６．０／３８．０／２４．０／２．０）、（３６．０／３８．０／２４．５／１．５）、（３６．０／３８．０／２５．０／１．０）、（３６．０／３８．５／２３．５／２．０）、（３６．０／３８．５／２４．０／１．５）、（３６．０／３８．５／２４．５／１．０）、（３６．０／３９．０／２３．０／２．０）、（３６．０／３９．０／２３．５／１．５）、（３６．０／３９．０／２４．０／１．０）、（３６．０／３９．５／２２．５／２．０）、（３６．０／３９．５／２３．０／１．５）、（３６．０／３９．５／２３．５／１．０）、（３６．０／４０．０／２２．０／２．０）、（３６．０／４０．０／２２．５／１．５）、（３６．０／４０．０／２３．０／１．０）、（３６．５／２６．５／３５．０／２．０）、（３６．５／２７．０／３４．５／２．０）、（３６．５／２７．０／３５．０／１．５）、（３６．５／２７．５／３４．０／２．０）、（３６．５／２７．５／３４．５／１．５）、（３６．５／２７．５／３５．０／１．０）、（３６．５／２８．０／３３．５／２．０）、（３６．５／２８．０／３４．０／１．５）、（３６．５／２８．０／３４．５／１．０）、（３６．５／２８．５／３３．０／２．０）、（３６．５／２８．５／３３．５／１．５）、（３６．５／２８．５／３４．０／１．０）、（３６．５／２９．０／３２．５／２．０）、（３６．５／２９．０／３３．０／１．５）、（３６．５／２９．０／３３．５／１ ．０）、（３６．５／２９．５／３２．０／２．０）、（３６．５／２９．５／３２．５／１．５）、（３６．５／２９．５／３３．０／１．０）、（３６．５／３０．０／３１．５／２．０）、（３６．５／３０．０／３２．０／１．５）、（３６．５／３０．０／３２．５／１．０）、（３６．５／３０．５／３１．０／２．０）、（３６．５／３０．５／３１．５／１．５）、（３６．５／３０．５／３２．０／１．０）、（３６．５／３１．０／３０．５／２．０）、（３６．５／３１．０／３１．０／１．５）、（３６．５／３１．０／３１．５／１．０）、（３６．５／３１．５／３０．０／２．０）、（３６．５／３１．５／３０．５／１．５）、（３６．５／３１．５／３１．０／１．０）、（３６．５／３２．０／２９．５／２．０）、（３６．５／３２．０／３０．０／１．５）、（３６．５／３２．０／３０．５／１．０）、（３６．５／３２．５／２９．０／２．０）、（３６．５／３２．５／２９．５／１．５）、（３６．５／３２．５／３０．０／１．０）、（３６．５／３３．０／２８．５／２．０）、（３６．５／３３．０／２９．０／１．５）、（３６．５／３３．０／２９．５／１．０）、（３６．５／３３．５／２８．０／２．０）、（３６．５／３３．５／２８．５／１．５）、（３６．５／３３．５／２９．０／１．０）、（３６．５／３４．０／２７．５／２．０）、（３６．５／３４．０／２８．０／１．５）、（３６．５／３４．０／２８．５／１．０）、（３６．５／３４．５／２７．０／２．０）、（３６．５／３４．５／２７．５／１．５）、（３６．５／３４．５／２８．０／１．０）、（３６．５／３５．０／２６．５／２．０）、（３６．５／３５．０／２７．０／１．５）、（３６．５／３５．０／２７．５／１．０）、（３６．５／３５．５／２６．０／２．０）、（３６．５／３５．５／２６．５／１．５）、（３６．５／３５．５／２７．０／１．０）、（３６．５／３６．０／２５．５／２．０）、（３６．５／３６．０／２６．０／１．５）、（３６．５／３６．０／２６．５／１．０）、（３６．５／３６．５／２５．０／２．０）、（３６．５／３６．５／２５．５／１．５）、（３６．５／３６．５／２６．０／１．０）、（３６．５／３７．０／２４．５／２．０）、（３６．５／３７．０／２５．０／１．５）、（３６．５／３７．０／２５．５／１．０）、（３６．５／３７．５／２４．０／２．０）、（３６．５／３７．５／２４．５／１．５）、（３６．５／３７．５／２５．０／１．０）、（３６．５／３８．０／２３．５／２．０）、（３６．５／３８．０／２４．０／１．５）、（３６．５／３８．０／２４．５／１．０）、（３６．５／３８．５／２３．０／２．０）、（３６．５／３８．５／２３．５／１．５）、（３６．５／３８．５／２４．０／１．０）、（３６．５／３９．０／２２．５／２．０）、（３６．５／３９．０／２３．０／１．５）、（３６．５／３９．０／２３．５／１．０）、（３６．５／３９．５／２２．０／２．０）、（３６．５／３９．５／２２．５／１．５）、（３６．５／３９．５／２３．０／１．０）、（３６．５／４０．０／２１．５／２．０）、（３６．５／４０．０／２２．０／１．５）、（３６．５／４０．０／２２．５／１．０）、（３７．０／２６．０／３５．０／２．０）、（３７．０／２６．５／３４．５／２．０）、（３７．０／２６．５／３５．０／１．５）、（３７．０／２７．０／３４．０／２．０）、（３７．０／２７．０／３４．５／１．５）、（３７．０／２７．０／３５．０／１．０）、（３７．０／２７．５／３３．５／２．０）、（３７．０／２７．５／３４．０／１．５）、（３７．０／２７．５／３４．５／１．０）、（３７．０／２８．０／３３．０／２．０）、（３７．０／２８．０／３３．５／１．５）、（３７．０／２８．０／３４．０／１．０）、（３７．０／２８．５／３２．５／２．０）、（３７．０／２８．５／３３．０／１．５）、（３７．０／２８．５／３３．５／１．０）、（３７．０／２９．０／３２．０／２．０）、（３７．０／２９．０／３２．５／１．５）、（３７．０／２９．０／３３．０／１．０）、（３７．０／２９．５／３１．５／２．０）、（３７．０／２９．５／３２．０／１．５）、（３７．０／２９．５／３２．５／１．０）、（３７．０／３０．０／３１．０／２．０）、（３７．０／３０．０／３１．５／１．５）、（３７．０／３０．０／３２．０／１．０）、（３７．０／３０．５／３０．５／２．０）、（３７．０／３０．５／３１．０／１．５）、（３７．０／３０．５／３１．５／１．０）、（３７．０／３１．０／３０．０／２．０）、（３７．０／３１．０／３０．５／１．５）、（３７．０／３１．０／３１．０／１．０）、（３７．０／３１．５／２９．５／２．０）、（３７．０／３１．５／３０．０／１．５）、（３７．０／３１．５／３０．５／１．０）、（３７．０／３２．０／２９．０／２．０）、（３７．０／３２．０／２９．５／１．５）、（３７．０／３２．０／３０．０／１．０）、（３７．０／３２．５／２８．５／２．０）、（３７．０／３２．５／２９．０／１．５）、（３７．０／３２．５／２９．５／１．０）、（３７．０／３３．０／２８．０／２．０）、（３７．０／３３．０／２８．５／１．５）、（３７．０／３３．０／２９．０／１．０）、（３７．０／３３．５／２７．５／２．０）、（３７．０／３３．５／２８．０／１．５）、（３７．０／３３．５／２８．５／１．０）、（３７．０／３４．０／２７．０／２．０）、（３７．０／３４．０／２７．５／１．５）、（３７．０／３４．０／２８．０／１．０）、（３７．０／３４．５／２６．５／２．０）、（３７．０／３４．５／２７．０／１．５）、（３７．０／３４．５／２７．５／１．０）、（３７．０／３５．０／２６．０／２．０）、（３７．０／３５．０／２６．５／１．５）、（３７．０／３５．０／２７．０／１．０）、（３７．０／３５．５／２５．５／２．０）、（３７．０／３５．５／２６．０／１．５）、（３７．０／３５．５／２６．５／１．０）、（３７．０／３６．０／２５．０／２．０）、（３７．０／３６．０／２５．５／１．５）、（３７．０／３６．０／２６．０／１．０）、（３７．０／３６．５／２４．５／２．０）、（３７．０／３６．５／２５．０／１．５）、（３７．０／３６．５／２５．５／１．０）、（３７．０／３７．０／２４．０／２．０）、（３７．０／３７．０／２４．５／１．５）、（３７．０／３７．０／２５．０／１．０）、（３７．０／３７．５／２３．５／２．０）、（３７．０／３７．５／２４．０／１．５）、（３７．０／３７．５／２４．５／１．０）、（３７．０／３８．０／２３．０／２．０）、（３７．０／３８．０／２３．５／１．５）、（３７．０／３８．０／２４．０／１．０）、（３７．０／３８．５／２２．５／２．０）、（３７．０／３８．５／２３．０／１．５）、（３７．０／３８．５／２３．５／１．０）、（３７．０／３９．０／２２．０／２．０）、（３７．０／３９．０／２２．５／１．５）、（３７．０／３９．０／２３．０／１．０）、（３７．０／３９．５／２１．５／２．０）、（３７．０／３９．５／２２．０／１．５）、（３７．０／３９．５／２２．５／１．０）、（３７．０／４０．０／２１．０／２．０）、（３７．０／４０．０／２１．５／１．５）、（３７．０／４０．０／２２．０／１．０）、（３７．５／２５．５／３５．０／２．０）、（３７．５／２６．０／３４．５／２．０）、（３７．５／２６．０／３５．０／１．５）、（３７．５／２６．５／３４．０／２．０）、（３７．５／２６．５／３４．５／１．５）、（３７．５／２６．５／３５．０／１．０）、（３７．５／２７．０／３３．５／２．０）、（３７．５／２７．０／３４．０／１．５）、（３７．５／２７．０／３４．５／１．０）、（３７．５／２７．５／３３．０／２．０）、（３７．５／２７．５／３３．５／１．５）、（３７．５／２７．５／３４．０／１．０）、（３７．５／２８．０／３２．５／２．０）、（３７．５／２８．０／３３．０／１．５）、（３７．５／２８．０／３３．５／１．０）、（３７．５／２８．５／３２．０／２．０）、（３７．５／２８．５／３２．５／１．５）、（３７．５／２８．５／３３．０／１．０）、（３７．５／２９．０／３１．５／２．０）、（３７．５／２９．０／３２．０／１．５）、（３７．５／２９．０／３２．５／１．０）、（３７．５／２９．５／３１．０／２．０）、（３７．５／２９．５／３１．５／１．５）、（３７．５／２９．５／３２．０／１．０）、（３７．５／３０．０／３０．５／２．０）、（３７．５／３０．０／３１．０／１．５）、（３７．５／３０．０／３１．５／１．０）、（３７．５／３０．５／３０．０／２．０）、（３７．５／３０．５／３０．５／１．５）、（３７．５／３０．５／３１．０／１．０）、（３７．５／３１．０／２９．５／２．０）、（３７．５／３１．０／３０．０／１．５）、（３７．５／３１．０／３０．５／１．０）、（３７．５／３１．５／２９．０／２．０）、（３７．５／３１．５／２９．５／１．５）、（３７．５／３１．５／３０．０／１．０）、（３７．５／３２．０／２８．５／２．０）、（３７．５／３２．０／２９．０／１．５）、（３７．５／３２．０／２９．５／１．０）、（３７．５／３２．５／２８．０／２．０）、（３７．５／３２．５／２８．５／１．５）、（３７．５／３２．５／２９．０／１．０）、（３７．５／３３．０／２７．５／２．０）、（３７．５／３３．０／２８．０／１．５）、（３７．５／３３．０／２８．５／１．０）、（３７．５／３３．５／２７．０／２．０）、（３７．５／３３．５／２７．５／１．５）、（３７．５／３３．５／２８．０／１．０）、（３７．５／３４．０／２６．５／２．０）、（３７．５／３４．０／２７．０／１．５）、（３７．５／３４．０／２７．５／１．０）、（３７．５／３４．５／２６．０／２．０）、（３７．５／３４．５／２６．５／１．５）、（３７．５／３４．５／２７．０／１．０）、（３７．５／３５．０／２５．５／２．０）、（３７．５／３５．０／２６．０／１．５）、（３７．５／３５．０／２６．５／１．０）、（３７．５／３５．５／２５．０／２．０）、（３７．５／３５．５／２５．５／１．５）、（３７．５／３５．５／２６．０／１．０）、（３７．５／３６．０／２４．５／２．０）、（３７．５／３６．０／２５．０／１．５）、（３７．５／３６．０／２５．５／１．０）、（３７．５／３６．５／２４．０／２．０）、（３７．５／３６．５／２４．５／１．５）、（３７．５／３６．５／２５．０／１．０）、（３７．５／３７．０／２３．５／２．０）、（３７．５／３７．０／２４．０／１．５）、（３７．５／３７．０／２４．５／１．０）、（３７．５／３７．５／２３．０／２．０）、（３７．５／３７．５／２３．５／１．５）、（３７．５／３７．５／２４．０／１．０）、（３７．５／３８．０／２２．５／２．０）、（３７．５／３８．０／２３．０／１．５）、（３７．５／３８．０／２３．５／１．０）、（３７．５／３８．５／２２．０／２．０）、（３７．５／３８．５／２２．５／１．５）、（３７．５／３８．５／２３．０／１．０）、（３７．５／３９．０／２１．５／２．０）、（３７．５／３９．０／２２．０／１．５）、（３７．５／３９．０／２２．５／１．０）、（３７．５／３９．５／２１．０／２．０）、（３７．５／３９．５／２１．５／１．５）、（３７．５／３９．５／２２．０／１．０）、（３７．５／４０．０／２０．５／２．０）、（３７．５／４０．０／２１．０／１．５）、（３７．５／４０．０／２１．５／１．０）、（３８．０／２５．０／３５．０／２．０）、（３８．０／２５．５／３４．５／２．０）、（３８．０／２５．５／３５．０／１．５）、（３８．０／２６．０／３４．０／２．０）、（３８．０／２６．０／３４．５／１．５）、（３８．０／２６．０／３５．０／１．０）、（３８．０／２６．５／３３． ５／２．０）、（３８．０／２６．５／３４．０／１．５）、（３８．０／２６．５／３４．５／１．０）、（３８．０／２７．０／３３．０／２．０）、（３８．０／２７．０／３３．５／１．５）、（３８．０／２７．０／３４．０／１．０）、（３８．０／２７．５／３２．５／２．０）、（３８．０／２７．５／３３．０／１．５）、（３８．０／２７．５／３３．５／１．０）、（３８．０／２８．０／３２．０／２．０）、（３８．０／２８．０／３２．５／１．５）、（３８．０／２８．０／３３．０／１．０）、（３８．０／２８．５／３１．５／２．０）、（３８．０／２８．５／３２．０／１．５）、（３８．０／２８．５／３２．５／１．０）、（３８．０／２９．０／３１．０／２．０）、（３８．０／２９．０／３１．５／１．５）、（３８．０／２９．０／３２．０／１．０）、（３８．０／２９．５／３０．５／２．０）、（３８．０／２９．５／３１．０／１．５）、（３８．０／２９．５／３１．５／１．０）、（３８．０／３０．０／３０．０／２．０）、（３８．０／３０．０／３０．５／１．５）、（３８．０／３０．０／３１．０／１．０）、（３８．０／３０．５／２９．５／２．０）、（３８．０／３０．５／３０．０／１．５）、（３８．０／３０．５／３０．５／１．０）、（３８．０／３１．０／２９．０／２．０）、（３８．０／３１．０／２９．５／１．５）、（３８．０／３１．０／３０．０／１．０）、（３８．０／３１．５／２８．５／２．０）、（３８．０／３１．５／２９．０／１．５）、（３８．０／３１．５／２９．５／１．０）、（３８．０／３２．０／２８．０／２．０）、（３８．０／３２．０／２８．５／１．５）、（３８．０／３２．０／２９．０／１．０）、（３８．０／３２．５／２７．５／２．０）、（３８．０／３２．５／２８．０／１．５）、（３８．０／３２．５／２８．５／１．０）、（３８．０／３３．０／２７．０／２．０）、（３８．０／３３．０／２７．５／１．５）、（３８．０／３３．０／２８．０／１．０）、（３８．０／３３．５／２６．５／２．０）、（３８．０／３３．５／２７．０／１．５）、（３８．０／３３．５／２７．５／１．０）、（３８．０／３４．０／２６．０／２．０）、（３８．０／３４．０／２６．５／１．５）、（３８．０／３４．０／２７．０／１．０）、（３８．０／３４．５／２５．５／２．０）、（３８．０／３４．５／２６．０／１．５）、（３８．０／３４．５／２６．５／１．０）、（３８．０／３５．０／２５．０／２．０）、（３８．０／３５．０／２５．５／１．５）、（３８．０／３５．０／２６．０／１．０）、（３８．０／３５．５／２４．５／２．０）、（３８．０／３５．５／２５．０／１．５）、（３８．０／３５．５／２５．５／１．０）、（３８．０／３６．０／２４．０／２．０）、（３８．０／３６．０／２４．５／１．５）、（３８．０／３６．０／２５．０／１．０）、（３８．０／３６．５／２３．５／２．０）、（３８．０／３６．５／２４．０／１．５）、（３８．０／３６．５／２４．５／１．０）、（３８．０／３７．０／２３．０／２．０）、（３８．０／３７．０／２３．５／１．５）、（３８．０／３７．０／２４．０／１．０）、（３８．０／３７．５／２２．５／２．０）、（３８．０／３７．５／２３．０／１．５）、（３８．０／３７．５／２３．５／１．０）、（３８．０／３８．０／２２．０／２．０）、（３８．０／３８．０／２２．５／１．５）、（３８．０／３８．０／２３．０／１．０）、（３８．０／３８．５／２１．５／２．０）、（３８．０／３８．５／２２．０／１．５）、（３８．０／３８．５／２２．５／１．０）、（３８．０／３９．０／２１．０／２．０）、（３８．０／３９．０／２１．５／１．５）、（３８．０／３９．０／２２．０／１．０）、（３８．０／３９．５／２０．５／２．０）、（３８．０／３９．５／２１．０／１．５）、（３８．０／３９．５／２１．５／１．０）、（３８．０／４０．０／２０．０／２．０）、（３８．０／４０．０／２０．５／１．５）、（３８．０／４０．０／２１．０／１．０）、（３８．５／２５．０／３４．５／２．０）、（３８．５／２５．０／３５．０／１．５）、（３８．５／２５．５／３４．０／２．０）、（３８．５／２５．５／３４．５／１．５）、（３８．５／２５．５／３５．０／１．０）、（３８．５／２６．０／３３．５／２．０）、（３８．５／２６．０／３４．０／１．５）、（３８．５／２６．０／３４．５／１．０）、（３８．５／２６．５／３３．０／２．０）、（３８．５／２６．５／３３．５／１．５）、（３８．５／２６．５／３４．０／１．０）、（３８．５／２７．０／３２．５／２．０）、（３８．５／２７．０／３３．０／１．５）、（３８．５／２７．０／３３．５／１．０）、（３８．５／２７．５／３２．０／２．０）、（３８．５／２７．５／３２．５／１．５）、（３８．５／２７．５／３３．０／１．０）、（３８．５／２８．０／３１．５／２．０）、（３８．５／２８．０／３２．０／１．５）、（３８．５／２８．０／３２．５／１．０）、（３８．５／２８．５／３１．０／２．０）、（３８．５／２８．５／３１．５／１．５）、（３８．５／２８．５／３２．０／１．０）、（３８．５／２９．０／３０．５／２．０）、（３８．５／２９．０／３１．０／１．５）、（３８．５／２９．０／３１．５／１．０）、（３８．５／２９．５／３０．０／２．０）、（３８．５／２９．５／３０．５／１．５）、（３８．５／２９．５／３１．０／１．０）、（３８．５／３０．０／２９．５／２．０）、（３８．５／３０．０／３０．０／１．５）、（３８．５／３０．０／３０．５／１．０）、（３８．５／３０．５／２９．０／２．０）、（３８．５／３０．５／２９．５／１．５）、（３８．５／３０．５／３０．０／１．０）、（３８．５／３１．０／２８．５／２．０）、（３８．５／３１．０／２９．０／１．５）、（３８．５／３１．０／２９．５／１．０）、（３８．５／３１．５／２８．０／２．０）、（３８．５／３１．５／２８．５／１．５）、（３８．５／３１．５／２９．０／１．０）、（３８．５／３２．０／２７．５／２．０）、（３８．５／３２．０／２８．０／１．５）、（３８．５／３２．０／２８．５／１．０）、（３８．５／３２．５／２７．０／２．０）、（３８．５／３２．５／２７．５／１．５）、（３８．５／３２．５／２８．０／１．０）、（３８．５／３３．０／２６．５／２．０）、（３８．５／３３．０／２７．０／１．５）、（３８．５／３３．０／２７．５／１．０）、（３８．５／３３．５／２６．０／２．０）、（３８．５／３３．５／２６．５／１．５）、（３８．５／３３．５／２７．０／１．０）、（３８．５／３４．０／２５．５／２．０）、（３８．５／３４．０／２６．０／１．５）、（３８．５／３４．０／２６．５／１．０）、（３８．５／３４．５／２５．０／２．０）、（３８．５／３４．５／２５．５／１．５）、（３８．５／３４．５／２６．０／１．０）、（３８．５／３５．０／２４．５／２．０）、（３８．５／３５．０／２５．０／１．５）、（３８．５／３５．０／２５．５／１．０）、（３８．５／３５．５／２４．０／２．０）、（３８．５／３５．５／２４．５／１．５）、（３８．５／３５．５／２５．０／１．０）、（３８．５／３６．０／２３．５／２．０）、（３８．５／３６．０／２４．０／１．５）、（３８．５／３６．０／２４．５／１．０）、（３８．５／３６．５／２３．０／２．０）、（３８．５／３６．５／２３．５／１．５）、（３８．５／３６．５／２４．０／１．０）、（３８．５／３７．０／２２．５／２．０）、（３８．５／３７．０／２３．０／１．５）、（３８．５／３７．０／２３．５／１．０）、（３８．５／３７．５／２２．０／２．０）、（３８．５／３７．５／２２．５／１．５）、（３８．５／３７．５／２３．０／１．０）、（３８．５／３８．０／２１．５／２．０）、（３８．５／３８．０／２２．０／１．５）、（３８．５／３８．０／２２．５／１．０）、（３８．５／３８．５／２１．０／２．０）、（３８．５／３８．５／２１．５／１．５）、（３８．５／３８．５／２２．０／１．０）、（３８．５／３９．０／２０．５／２．０）、（３８．５／３９．０／２１．０／１．５）、（３８．５／３９．０／２１．５／１．０）、（３８．５／３９．５／２０．０／２．０）、（３８．５／３９．５／２０．５／１．５）、（３８．５／３９．５／２１．０／１．０）、（３８．５／４０．０／１９．５／２．０）、（３８．５／４０．０／２０．０／１．５）、（３８．５／４０．０／２０．５／１．０）、（３９．０／２５．０／３４．０／２．０）、（３９．０／２５．０／３４．５／１．５）、（３９．０／２５．０／３５．０／１．０）、（３９．０／２５．５／３３．５／２．０）、（３９．０／２５．５／３４．０／１．５）、（３９．０／２５．５／３４．５／１．０）、（３９．０／２６．０／３３．０／２．０）、（３９．０／２６．０／３３．５／１．５）、（３９．０／２６．０／３４．０／１．０）、（３９．０／２６．５／３２．５／２．０）、（３９．０／２６．５／３３．０／１．５）、（３９．０／２６．５／３３．５／１．０）、（３９．０／２７．０／３２．０／２．０）、（３９．０／２７．０／３２．５／１．５）、（３９．０／２７．０／３３．０／１．０）、（３９．０／２７．５／３１．５／２．０）、（３９．０／２７．５／３２．０／１．５）、（３９．０／２７．５／３２．５／１．０）、（３９．０／２８．０／３１．０／２．０）、（３９．０／２８．０／３１．５／１．５）、（３９．０／２８．０／３２．０／１．０）、（３９．０／２８．５／３０．５／２．０）、（３９．０／２８．５／３１．０／１．５）、（３９．０／２８．５／３１．５／１．０）、（３９．０／２９．０／３０．０／２．０）、（３９．０／２９．０／３０．５／１．５）、（３９．０／２９．０／３１．０／１．０）、（３９．０／２９．５／２９．５／２．０）、（３９．０／２９．５／３０．０／１．５）、（３９．０／２９．５／３０．５／１．０）、（３９．０／３０．０／２９．０／２．０）、（３９．０／３０．０／２９．５／１．５）、（３９．０／３０．０／３０．０／１．０）、（３９．０／３０．５／２８．５／２．０）、（３９．０／３０．５／２９．０／１．５）、（３９．０／３０．５／２９．５／１．０）、（３９．０／３１．０／２８．０／２．０）、（３９．０／３１．０／２８．５／１．５）、（３９．０／３１．０／２９．０／１．０）、（３９．０／３１．５／２７．５／２．０）、（３９．０／３１．５／２８．０／１．５）、（３９．０／３１．５／２８．５／１．０）、（３９．０／３２．０／２７．０／２．０）、（３９．０／３２．０／２７．５／１．５）、（３９．０／３２．０／２８．０／１．０）、（３９．０／３２．５／２６．５／２．０）、（３９．０／３２．５／２７．０／１．５）、（３９．０／３２．５／２７．５／１．０）、（３９．０／３３．０／２６．０／２．０）、（３９．０／３３．０／２６．５／１．５）、（３９．０／３３．０／２７．０／１．０）、（３９．０／３３．５／２５．５／２．０）、（３９．０／３３．５／２６．０／１．５）、（３９．０／３３．５／２６．５／１．０）、（３９．０／３４．０／２５．０／２．０）、（３９．０／３４．０／２５．５／１．５）、（３９．０／３４．０／２６．０／１．０）、（３９．０／３４．５／２４．５／２．０）、（３９．０／３４．５／２５．０／１．５）、（３９．０／３４．５／２５．５／１．０）、（３９．０／３５．０／２４．０／２．０）、（３９．０／３５．０／２４．５／１．５）、（３９．０／３５．０／２５．０／１．０）、（３９．０／３５．５／２３．５／２．０）、（３９．０／３５．５／２４．０／１．５）、（３９．０／３５．５／２４．５／１．０）、（３９．０／３６．０／２３．０／２．０）、（３９．０／３６．０／２３．５／１．５）、（３９．０／３６．０／ ２４．０／１．０）、（３９．０／３６．５／２２．５／２．０）、（３９．０／３６．５／２３．０／１．５）、（３９．０／３６．５／２３．５／１．０）、（３９．０／３７．０／２２．０／２．０）、（３９．０／３７．０／２２．５／１．５）、（３９．０／３７．０／２３．０／１．０）、（３９．０／３７．５／２１．５／２．０）、（３９．０／３７．５／２２．０／１．５）、（３９．０／３７．５／２２．５／１．０）、（３９．０／３８．０／２１．０／２．０）、（３９．０／３８．０／２１．５／１．５）、（３９．０／３８．０／２２．０／１．０）、（３９．０／３８．５／２０．５／２．０）、（３９．０／３８．５／２１．０／１．５）、（３９．０／３８．５／２１．５／１．０）、（３９．０／３９．０／２０．０／２．０）、（３９．０／３９．０／２０．５／１．５）、（３９．０／３９．０／２１．０／１．０）、（３９．０／３９．５／１９．５／２．０）、（３９．０／３９．５／２０．０／１．５）、（３９．０／３９．５／２０．５／１．０）、（３９．０／４０．０／１９．０／２．０）、（３９．０／４０．０／１９．５／１．５）、（３９．０／４０．０／２０．０／１．０）、（３９．５／２５．０／３３．５／２．０）、（３９．５／２５．０／３４．０／１．５）、（３９．５／２５．０／３４．５／１．０）、（３９．５／２５．５／３３．０／２．０）、（３９．５／２５．５／３３．５／１．５）、（３９．５／２５．５／３４．０／１．０）、（３９．５／２６．０／３２．５／２．０）、（３９．５／２６．０／３３．０／１．５）、（３９．５／２６．０／３３．５／１．０）、（３９．５／２６．５／３２．０／２．０）、（３９．５／２６．５／３２．５／１．５）、（３９．５／２６．５／３３．０／１．０）、（３９．５／２７．０／３１．５／２．０）、（３９．５／２７．０／３２．０／１．５）、（３９．５／２７．０／３２．５／１．０）、（３９．５／２７．５／３１．０／２．０）、（３９．５／２７．５／３１．５／１．５）、（３９．５／２７．５／３２．０／１．０）、（３９．５／２８．０／３０．５／２．０）、（３９．５／２８．０／３１．０／１．５）、（３９．５／２８．０／３１．５／１．０）、（３９．５／２８．５／３０．０／２．０）、（３９．５／２８．５／３０．５／１．５）、（３９．５／２８．５／３１．０／１．０）、（３９．５／２９．０／２９．５／２．０）、（３９．５／２９．０／３０．０／１．５）、（３９．５／２９．０／３０．５／１．０）、（３９．５／２９．５／２９．０／２．０）、（３９．５／２９．５／２９．５／１．５）、（３９．５／２９．５／３０．０／１．０）、（３９．５／３０．０／２８．５／２．０）、（３９．５／３０．０／２９．０／１．５）、（３９．５／３０．０／２９．５／１．０）、（３９．５／３０．５／２８．０／２．０）、（３９．５／３０．５／２８．５／１．５）、（３９．５／３０．５／２９．０／１．０）、（３９．５／３１．０／２７．５／２．０）、（３９．５／３１．０／２８．０／１．５）、（３９．５／３１．０／２８．５／１．０）、（３９．５／３１．５／２７．０／２．０）、（３９．５／３１．５／２７．５／１．５）、（３９．５／３１．５／２８．０／１．０）、（３９．５／３２．０／２６．５／２．０）、（３９．５／３２．０／２７．０／１．５）、（３９．５／３２．０／２７．５／１．０）、（３９．５／３２．５／２６．０／２．０）、（３９．５／３２．５／２６．５／１．５）、（３９．５／３２．５／２７．０／１．０）、（３９．５／３３．０／２５．５／２．０）、（３９．５／３３．０／２６．０／１．５）、（３９．５／３３．０／２６．５／１．０）、（３９．５／３３．５／２５．０／２．０）、（３９．５／３３．５／２５．５／１．５）、（３９．５／３３．５／２６．０／１．０）、（３９．５／３４．０／２４．５／２．０）、（３９．５／３４．０／２５．０／１．５）、（３９．５／３４．０／２５．５／１．０）、（３９．５／３４．５／２４．０／２．０）、（３９．５／３４．５／２４．５／１．５）、（３９．５／３４．５／２５．０／１．０）、（３９．５／３５．０／２３．５／２．０）、（３９．５／３５．０／２４．０／１．５）、（３９．５／３５．０／２４．５／１．０）、（３９．５／３５．５／２３．０／２．０）、（３９．５／３５．５／２３．５／１．５）、（３９．５／３５．５／２４．０／１．０）、（３９．５／３６．０／２２．５／２．０）、（３９．５／３６．０／２３．０／１．５）、（３９．５／３６．０／２３．５／１．０）、（３９．５／３６．５／２２．０／２．０）、（３９．５／３６．５／２２．５／１．５）、（３９．５／３６．５／２３．０／１．０）、（３９．５／３７．０／２１．５／２．０）、（３９．５／３７．０／２２．０／１．５）、（３９．５／３７．０／２２．５／１．０）、（３９．５／３７．５／２１．０／２．０）、（３９．５／３７．５／２１．５／１．５）、（３９．５／３７．５／２２．０／１．０）、（３９．５／３８．０／２０．５／２．０）、（３９．５／３８．０／２１．０／１．５）、（３９．５／３８．０／２１．５／１．０）、（３９．５／３８．５／２０．０／２．０）、（３９．５／３８．５／２０．５／１．５）、（３９．５／３８．５／２１．０／１．０）、（３９．５／３９．０／１９．５／２．０）、（３９．５／３９．０／２０．０／１．５）、（３９．５／３９．０／２０．５／１．０）、（３９．５／３９．５／１９．０／２．０）、（３９．５／３９．５／１９．５／１．５）、（３９．５／３９．５／２０．０／１．０）、（３９．５／４０．０／１８．５／２．０）、（３９．５／４０．０／１９．０／１．５）、（３９．５／４０．０／１９．５／１．０）、（４０．０／２５．０／３３．０／２．０）、（４０．０／２５．０／３３．５／１．５）、（４０．０／２５．０／３４．０／１．０）、（４０．０／２５．５／３２．５／２．０）、（４０．０／２５．５／３３．０／１．５）、（４０．０／２５．５／３３．５／１．０）、（４０．０／２６．０／３２．０／２．０）、（４０．０／２６．０／３２．５／１．５）、（４０．０／２６．０／３３．０／１．０）、（４０．０／２６．５／３１．５／２．０）、（４０．０／２６．５／３２．０／１．５）、（４０．０／２６．５／３２．５／１．０）、（４０．０／２７．０／３１．０／２．０）、（４０．０／２７．０／３１．５／１．５）、（４０．０／２７．０／３２．０／１．０）、（４０．０／２７．５／３０．５／２．０）、（４０．０／２７．５／３１．０／１．５）、（４０．０／２７．５／３１．５／１．０）、（４０．０／２８．０／３０．０／２．０）、（４０．０／２８．０／３０．５／１．５）、（４０．０／２８．０／３１．０／１．０）、（４０．０／２８．５／２９．５／２．０）、（４０．０／２８．５／３０．０／１．５）、（４０．０／２８．５／３０．５／１．０）、（４０．０／２９．０／２９．０／２．０）、（４０．０／２９．０／２９．５／１．５）、（４０．０／２９．０／３０．０／１．０）、（４０．０／２９．５／２８．５／２．０）、（４０．０／２９．５／２９．０／１．５）、（４０．０／２９．５／２９．５／１．０）、（４０．０／３０．０／２８．０／２．０）、（４０．０／３０．０／２８．５／１．５）、（４０．０／３０．０／２９．０／１．０）、（４０．０／３０．５／２７．５／２．０）、（４０．０／３０．５／２８．０／１．５）、（４０．０／３０．５／２８．５／１．０）、（４０．０／３１．０／２７．０／２．０）、（４０．０／３１．０／２７．５／１．５）、（４０．０／３１．０／２８．０／１．０）、（４０．０／３１．５／２６．５／２．０）、（４０．０／３１．５／２７．０／１．５）、（４０．０／３１．５／２７．５／１．０）、（４０．０／３２．０／２６．０／２．０）、（４０．０／３２．０／２６．５／１．５）、（４０．０／３２．０／２７．０／１．０）、（４０．０／３２．５／２５．５／２．０）、（４０．０／３２．５／２６．０／１．５）、（４０．０／３２．５／２６．５／１．０）、（４０．０／３３．０／２５．０／２．０）、（４０．０／３３．０／２５．５／１．５）、（４０．０／３３．０／２６．０／１．０）、（４０．０／３３．５／２４．５／２．０）、（４０．０／３３．５／２５．０／１．５）、（４０．０／３３．５／２５．５／１．０）、（４０．０／３４．０／２４．０／２．０）、（４０．０／３４．０／２４．５／１．５）、（４０．０／３４．０／２５．０／１．０）、（４０．０／３４．５／２３．５／２．０）、（４０．０／３４．５／２４．０／１．５）、（４０．０／３４．５／２４．５／１．０）、（４０．０／３５．０／２３．０／２．０）、（４０．０／３５．０／２３．５／１．５）、（４０．０／３５．０／２４．０／１．０）、（４０．０／３５．５／２２．５／２．０）、（４０．０／３５．５／２３．０／１．５）、（４０．０／３５．５／２３．５／１．０）、（４０．０／３６．０／２２．０／２．０）、（４０．０／３６．０／２２．５／１．５）、（４０．０／３６．０／２３．０／１．０）、（４０．０／３６．５／２１．５／２．０）、（４０．０／３６．５／２２．０／１．５）、（４０．０／３６．５／２２．５／１．０）、（４０．０／３７．０／２１．０／２．０）、（４０．０／３７．０／２１．５／１．５）、（４０．０／３７．０／２２．０／１．０）、（４０．０／３７．５／２０．５／２．０）、（４０．０／３７．５／２１．０／１．５）、（４０．０／３７．５／２１．５／１．０）、（４０．０／３８．０／２０．０／２．０）、（４０．０／３８．０／２０．５／１．５）、（４０．０／３８．０／２１．０／１．０）、（４０．０／３８．５／１９．５／２．０）、（４０．０／３８．５／２０．０／１．５）、（４０．０／３８．５／２０．５／１．０）、（４０．０／３９．０／１９．０／２．０）、（４０．０／３９．０／１９．５／１．５）、（４０．０／３９．０／２０．０／１．０）、（４０．０／３９．５／１８．５／２．０）、（４０．０／３９．５／１９．０／１．５）、（４０．０／３９．５／１９．５／１．０）、（４０．０／４０．０／１８．０／２．０）、（４０．０／４０．０／１８．５／１．５）、（４０．０／４０．０／１９．０／１．０）、（４０．５／２５．０／３２．５／２．０）、（４０．５／２５．０／３３．０／１．５）、（４０．５／２５．０／３３．５／１．０）、（４０．５／２５．５／３２．０／２．０）、（４０．５／２５．５／３２．５／１．５）、（４０．５／２５．５／３３．０／１．０）、（４０．５／２６．０／３１．５／２．０）、（４０．５／２６．０／３２．０／１．５）、（４０．５／２６．０／３２．５／１．０）、（４０．５／２６．５／３１．０／２．０）、（４０．５／２６．５／３１．５／１．５）、（４０．５／２６．５／３２．０／１．０）、（４０．５／２７．０／３０．５／２．０）、（４０．５／２７．０／３１．０／１．５）、（４０．５／２７．０／３１．５／１．０）、（４０．５／２７．５／３０．０／２．０）、（４０．５／２７．５／３０．５／１．５）、（４０．５／２７．５／３１．０／１．０）、（４０．５／２８．０／２９．５／２．０）、（４０．５／２８．０／３０．０／１．５）、（４０．５／２８．０／３０．５／１．０）、（４０．５／２８．５／２９．０／２．０）、（４０．５／２８．５／２９．５／１．５）、（４０．５／２８．５／３０．０／１．０）、（４０．５／２９．０／２８．５／２．０）、（４０．５／２９．０／２９．０／１．５）、（４０．５／２９．０／２９．５／１．０）、（４０．５／２９．５／２８．０／２．０）、（４０．５／２９．５／２８．５／１．５）、（４０．５／２９．５／２９．０／１．０）、（４０．５／３０．０／２７．５／２．０）、（４０．５／３０．０／２８．０／１．５）、（４０．５／３０．０／２８．５／１．０）、（４０．５／３０ ．５／２７．０／２．０）、（４０．５／３０．５／２７．５／１．５）、（４０．５／３０．５／２８．０／１．０）、（４０．５／３１．０／２６．５／２．０）、（４０．５／３１．０／２７．０／１．５）、（４０．５／３１．０／２７．５／１．０）、（４０．５／３１．５／２６．０／２．０）、（４０．５／３１．５／２６．５／１．５）、（４０．５／３１．５／２７．０／１．０）、（４０．５／３２．０／２５．５／２．０）、（４０．５／３２．０／２６．０／１．５）、（４０．５／３２．０／２６．５／１．０）、（４０．５／３２．５／２５．０／２．０）、（４０．５／３２．５／２５．５／１．５）、（４０．５／３２．５／２６．０／１．０）、（４０．５／３３．０／２４．５／２．０）、（４０．５／３３．０／２５．０／１．５）、（４０．５／３３．０／２５．５／１．０）、（４０．５／３３．５／２４．０／２．０）、（４０．５／３３．５／２４．５／１．５）、（４０．５／３３．５／２５．０／１．０）、（４０．５／３４．０／２３．５／２．０）、（４０．５／３４．０／２４．０／１．５）、（４０．５／３４．０／２４．５／１．０）、（４０．５／３４．５／２３．０／２．０）、（４０．５／３４．５／２３．５／１．５）、（４０．５／３４．５／２４．０／１．０）、（４０．５／３５．０／２２．５／２．０）、（４０．５／３５．０／２３．０／１．５）、（４０．５／３５．０／２３．５／１．０）、（４０．５／３５．５／２２．０／２．０）、（４０．５／３５．５／２２．５／１．５）、（４０．５／３５．５／２３．０／１．０）、（４０．５／３６．０／２１．５／２．０）、（４０．５／３６．０／２２．０／１．５）、（４０．５／３６．０／２２．５／１．０）、（４０．５／３６．５／２１．０／２．０）、（４０．５／３６．５／２１．５／１．５）、（４０．５／３６．５／２２．０／１．０）、（４０．５／３７．０／２０．５／２．０）、（４０．５／３７．０／２１．０／１．５）、（４０．５／３７．０／２１．５／１．０）、（４０．５／３７．５／２０．０／２．０）、（４０．５／３７．５／２０．５／１．５）、（４０．５／３７．５／２１．０／１．０）、（４０．５／３８．０／１９．５／２．０）、（４０．５／３８．０／２０．０／１．５）、（４０．５／３８．０／２０．５／１．０）、（４０．５／３８．５／１９．０／２．０）、（４０．５／３８．５／１９．５／１．５）、（４０．５／３８．５／２０．０／１．０）、（４０．５／３９．０／１８．５／２．０）、（４０．５／３９．０／１９．０／１．５）、（４０．５／３９．０／１９．５／１．０）、（４０．５／３９．５／１８．０／２．０）、（４０．５／３９．５／１８．５／１．５）、（４０．５／３９．５／１９．０／１．０）、（４０．５／４０．０／１７．５／２．０）、（４０．５／４０．０／１８．０／１．５）、（４０．５／４０．０／１８．５／１．０）、（４１．０／２５．０／３２．０／２．０）、（４１．０／２５．０／３２．５／１．５）、（４１．０／２５．０／３３．０／１．０）、（４１．０／２５．５／３１．５／２．０）、（４１．０／２５．５／３２．０／１．５）、（４１．０／２５．５／３２．５／１．０）、（４１．０／２６．０／３１．０／２．０）、（４１．０／２６．０／３１．５／１．５）、（４１．０／２６．０／３２．０／１．０）、（４１．０／２６．５／３０．５／２．０）、（４１．０／２６．５／３１．０／１．５）、（４１．０／２６．５／３１．５／１．０）、（４１．０／２７．０／３０．０／２．０）、（４１．０／２７．０／３０．５／１．５）、（４１．０／２７．０／３１．０／１．０）、（４１．０／２７．５／２９．５／２．０）、（４１．０／２７．５／３０．０／１．５）、（４１．０／２７．５／３０．５／１．０）、（４１．０／２８．０／２９．０／２．０）、（４１．０／２８．０／２９．５／１．５）、（４１．０／２８．０／３０．０／１．０）、（４１．０／２８．５／２８．５／２．０）、（４１．０／２８．５／２９．０／１．５）、（４１．０／２８．５／２９．５／１．０）、（４１．０／２９．０／２８．０／２．０）、（４１．０／２９．０／２８．５／１．５）、（４１．０／２９．０／２９．０／１．０）、（４１．０／２９．５／２７．５／２．０）、（４１．０／２９．５／２８．０／１．５）、（４１．０／２９．５／２８．５／１．０）、（４１．０／３０．０／２７．０／２．０）、（４１．０／３０．０／２７．５／１．５）、（４１．０／３０．０／２８．０／１．０）、（４１．０／３０．５／２６．５／２．０）、（４１．０／３０．５／２７．０／１．５）、（４１．０／３０．５／２７．５／１．０）、（４１．０／３１．０／２６．０／２．０）、（４１．０／３１．０／２６．５／１．５）、（４１．０／３１．０／２７．０／１．０）、（４１．０／３１．５／２５．５／２．０）、（４１．０／３１．５／２６．０／１．５）、（４１．０／３１．５／２６．５／１．０）、（４１．０／３２．０／２５．０／２．０）、（４１．０／３２．０／２５．５／１．５）、（４１．０／３２．０／２６．０／１．０）、（４１．０／３２．５／２４．５／２．０）、（４１．０／３２．５／２５．０／１．５）、（４１．０／３２．５／２５．５／１．０）、（４１．０／３３．０／２４．０／２．０）、（４１．０／３３．０／２４．５／１．５）、（４１．０／３３．０／２５．０／１．０）、（４１．０／３３．５／２３．５／２．０）、（４１．０／３３．５／２４．０／１．５）、（４１．０／３３．５／２４．５／１．０）、（４１．０／３４．０／２３．０／２．０）、（４１．０／３４．０／２３．５／１．５）、（４１．０／３４．０／２４．０／１．０）、（４１．０／３４．５／２２．５／２．０）、（４１．０／３４．５／２３．０／１．５）、（４１．０／３４．５／２３．５／１．０）、（４１．０／３５．０／２２．０／２．０）、（４１．０／３５．０／２２．５／１．５）、（４１．０／３５．０／２３．０／１．０）、（４１．０／３５．５／２１．５／２．０）、（４１．０／３５．５／２２．０／１．５）、（４１．０／３５．５／２２．５／１．０）、（４１．０／３６．０／２１．０／２．０）、（４１．０／３６．０／２１．５／１．５）、（４１．０／３６．０／２２．０／１．０）、（４１．０／３６．５／２０．５／２．０）、（４１．０／３６．５／２１．０／１．５）、（４１．０／３６．５／２１．５／１．０）、（４１．０／３７．０／２０．０／２．０）、（４１．０／３７．０／２０．５／１．５）、（４１．０／３７．０／２１．０／１．０）、（４１．０／３７．５／１９．５／２．０）、（４１．０／３７．５／２０．０／１．５）、（４１．０／３７．５／２０．５／１．０）、（４１．０／３８．０／１９．０／２．０）、（４１．０／３８．０／１９．５／１．５）、（４１．０／３８．０／２０．０／１．０）、（４１．０／３８．５／１８．５／２．０）、（４１．０／３８．５／１９．０／１．５）、（４１．０／３８．５／１９．５／１．０）、（４１．０／３９．０／１８．０／２．０）、（４１．０／３９．０／１８．５／１．５）、（４１．０／３９．０／１９．０／１．０）、（４１．０／３９．５／１７．５／２．０）、（４１．０／３９．５／１８．０／１．５）、（４１．０／３９．５／１８．５／１．０）、（４１．０／４０．０／１７．０／２．０）、（４１．０／４０．０／１７．５／１．５）、（４１．０／４０．０／１８．０／１．０）、（４１．５／２５．０／３１．５／２．０）、（４１．５／２５．０／３２．０／１．５）、（４１．５／２５．０／３２．５／１．０）、（４１．５／２５．５／３１．０／２．０）、（４１．５／２５．５／３１．５／１．５）、（４１．５／２５．５／３２．０／１．０）、（４１．５／２６．０／３０．５／２．０）、（４１．５／２６．０／３１．０／１．５）、（４１．５／２６．０／３１．５／１．０）、（４１．５／２６．５／３０．０／２．０）、（４１．５／２６．５／３０．５／１．５）、（４１．５／２６．５／３１．０／１．０）、（４１．５／２７．０／２９．５／２．０）、（４１．５／２７．０／３０．０／１．５）、（４１．５／２７．０／３０．５／１．０）、（４１．５／２７．５／２９．０／２．０）、（４１．５／２７．５／２９．５／１．５）、（４１．５／２７．５／３０．０／１．０）、（４１．５／２８．０／２８．５／２．０）、（４１．５／２８．０／２９．０／１．５）、（４１．５／２８．０／２９．５／１．０）、（４１．５／２８．５／２８．０／２．０）、（４１．５／２８．５／２８．５／１．５）、（４１．５／２８．５／２９．０／１．０）、（４１．５／２９．０／２７．５／２．０）、（４１．５／２９．０／２８．０／１．５）、（４１．５／２９．０／２８．５／１．０）、（４１．５／２９．５／２７．０／２．０）、（４１．５／２９．５／２７．５／１．５）、（４１．５／２９．５／２８．０／１．０）、（４１．５／３０．０／２６．５／２．０）、（４１．５／３０．０／２７．０／１．５）、（４１．５／３０．０／２７．５／１．０）、（４１．５／３０．５／２６．０／２．０）、（４１．５／３０．５／２６．５／１．５）、（４１．５／３０．５／２７．０／１．０）、（４１．５／３１．０／２５．５／２．０）、（４１．５／３１．０／２６．０／１．５）、（４１．５／３１．０／２６．５／１．０）、（４１．５／３１．５／２５．０／２．０）、（４１．５／３１．５／２５．５／１．５）、（４１．５／３１．５／２６．０／１．０）、（４１．５／３２．０／２４．５／２．０）、（４１．５／３２．０／２５．０／１．５）、（４１．５／３２．０／２５．５／１．０）、（４１．５／３２．５／２４．０／２．０）、（４１．５／３２．５／２４．５／１．５）、（４１．５／３２．５／２５．０／１．０）、（４１．５／３３．０／２３．５／２．０）、（４１．５／３３．０／２４．０／１．５）、（４１．５／３３．０／２４．５／１．０）、（４１．５／３３．５／２３．０／２．０）、（４１．５／３３．５／２３．５／１．５）、（４１．５／３３．５／２４．０／１．０）、（４１．５／３４．０／２２．５／２．０）、（４１．５／３４．０／２３．０／１．５）、（４１．５／３４．０／２３．５／１．０）、（４１．５／３４．５／２２．０／２．０）、（４１．５／３４．５／２２．５／１．５）、（４１．５／３４．５／２３．０／１．０）、（４１．５／３５．０／２１．５／２．０）、（４１．５／３５．０／２２．０／１．５）、（４１．５／３５．０／２２．５／１．０）、（４１．５／３５．５／２１．０／２．０）、（４１．５／３５．５／２１．５／１．５）、（４１．５／３５．５／２２．０／１．０）、（４１．５／３６．０／２０．５／２．０）、（４１．５／３６．０／２１．０／１．５）、（４１．５／３６．０／２１．５／１．０）、（４１．５／３６．５／２０．０／２．０）、（４１．５／３６．５／２０．５／１．５）、（４１．５／３６．５／２１．０／１．０）、（４１．５／３７．０／１９．５／２．０）、（４１．５／３７．０／２０．０／１．５）、（４１．５／３７．０／２０．５／１．０）、（４１．５／３７．５／１９．０／２．０）、（４１．５／３７．５／１９．５／１．５）、（４１．５／３７．５／２０．０／１．０）、（４１．５／３８．０／１８．５／２．０）、（４１．５／３８．０／１９．０／１．５）、（４１．５／３８．０／１９．５／１．０）、（４１．５／３８．５／１８．０／２．０）、（４１．５／３８．５／１８．５／１．５）、（４１．５／３８．５／１９．０／１．０）、（４１．５／３９．０／１７．５／２．０）、（４１．５／３９．０／１８．０／１．５）、（４１．５／３９．０／１８．５／１．０）、（４１．５／３９．５／１７．０／２．０）、（４１．５／３９．５／１７．５／１．５）、（４１．５／３９．５／１８．０／１．０）、（４１．５／４０．０／１６．５／２．０）、（４１．５ ／４０．０／１７．０／１．５）、（４１．５／４０．０／１７．５／１．０）、（４２．０／２５．０／３１．０／２．０）、（４２．０／２５．０／３１．５／１．５）、（４２．０／２５．０／３２．０／１．０）、（４２．０／２５．５／３０．５／２．０）、（４２．０／２５．５／３１．０／１．５）、（４２．０／２５．５／３１．５／１．０）、（４２．０／２６．０／３０．０／２．０）、（４２．０／２６．０／３０．５／１．５）、（４２．０／２６．０／３１．０／１．０）、（４２．０／２６．５／２９．５／２．０）、（４２．０／２６．５／３０．０／１．５）、（４２．０／２６．５／３０．５／１．０）、（４２．０／２７．０／２９．０／２．０）、（４２．０／２７．０／２９．５／１．５）、（４２．０／２７．０／３０．０／１．０）、（４２．０／２７．５／２８．５／２．０）、（４２．０／２７．５／２９．０／１．５）、（４２．０／２７．５／２９．５／１．０）、（４２．０／２８．０／２８．０／２．０）、（４２．０／２８．０／２８．５／１．５）、（４２．０／２８．０／２９．０／１．０）、（４２．０／２８．５／２７．５／２．０）、（４２．０／２８．５／２８．０／１．５）、（４２．０／２８．５／２８．５／１．０）、（４２．０／２９．０／２７．０／２．０）、（４２．０／２９．０／２７．５／１．５）、（４２．０／２９．０／２８．０／１．０）、（４２．０／２９．５／２６．５／２．０）、（４２．０／２９．５／２７．０／１．５）、（４２．０／２９．５／２７．５／１．０）、（４２．０／３０．０／２６．０／２．０）、（４２．０／３０．０／２６．５／１．５）、（４２．０／３０．０／２７．０／１．０）、（４２．０／３０．５／２５．５／２．０）、（４２．０／３０．５／２６．０／１．５）、（４２．０／３０．５／２６．５／１．０）、（４２．０／３１．０／２５．０／２．０）、（４２．０／３１．０／２５．５／１．５）、（４２．０／３１．０／２６．０／１．０）、（４２．０／３１．５／２４．５／２．０）、（４２．０／３１．５／２５．０／１．５）、（４２．０／３１．５／２５．５／１．０）、（４２．０／３２．０／２４．０／２．０）、（４２．０／３２．０／２４．５／１．５）、（４２．０／３２．０／２５．０／１．０）、（４２．０／３２．５／２３．５／２．０）、（４２．０／３２．５／２４．０／１．５）、（４２．０／３２．５／２４．５／１．０）、（４２．０／３３．０／２３．０／２．０）、（４２．０／３３．０／２３．５／１．５）、（４２．０／３３．０／２４．０／１．０）、（４２．０／３３．５／２２．５／２．０）、（４２．０／３３．５／２３．０／１．５）、（４２．０／３３．５／２３．５／１．０）、（４２．０／３４．０／２２．０／２．０）、（４２．０／３４．０／２２．５／１．５）、（４２．０／３４．０／２３．０／１．０）、（４２．０／３４．５／２１．５／２．０）、（４２．０／３４．５／２２．０／１．５）、（４２．０／３４．５／２２．５／１．０）、（４２．０／３５．０／２１．０／２．０）、（４２．０／３５．０／２１．５／１．５）、（４２．０／３５．０／２２．０／１．０）、（４２．０／３５．５／２０．５／２．０）、（４２．０／３５．５／２１．０／１．５）、（４２．０／３５．５／２１．５／１．０）、（４２．０／３６．０／２０．０／２．０）、（４２．０／３６．０／２０．５／１．５）、（４２．０／３６．０／２１．０／１．０）、（４２．０／３６．５／１９．５／２．０）、（４２．０／３６．５／２０．０／１．５）、（４２．０／３６．５／２０．５／１．０）、（４２．０／３７．０／１９．０／２．０）、（４２．０／３７．０／１９．５／１．５）、（４２．０／３７．０／２０．０／１．０）、（４２．０／３７．５／１８．５／２．０）、（４２．０／３７．５／１９．０／１．５）、（４２．０／３７．５／１９．５／１．０）、（４２．０／３８．０／１８．０／２．０）、（４２．０／３８．０／１８．５／１．５）、（４２．０／３８．０／１９．０／１．０）、（４２．０／３８．５／１７．５／２．０）、（４２．０／３８．５／１８．０／１．５）、（４２．０／３８．５／１８．５／１．０）、（４２．０／３９．０／１７．０／２．０）、（４２．０／３９．０／１７．５／１．５）、（４２．０／３９．０／１８．０／１．０）、（４２．０／３９．５／１６．５／２．０）、（４２．０／３９．５／１７．０／１．５）、（４２．０／３９．５／１７．５／１．０）、（４２．０／４０．０／１６．０／２．０）、（４２．０／４０．０／１６．５／１．５）、（４２．０／４０．０／１７．０／１．０）、（４２．５／２５．０／３０．５／２．０）、（４２．５／２５．０／３１．０／１．５）、（４２．５／２５．０／３１．５／１．０）、（４２．５／２５．５／３０．０／２．０）、（４２．５／２５．５／３０．５／１．５）、（４２．５／２５．５／３１．０／１．０）、（４２．５／２６．０／２９．５／２．０）、（４２．５／２６．０／３０．０／１．５）、（４２．５／２６．０／３０．５／１．０）、（４２．５／２６．５／２９．０／２．０）、（４２．５／２６．５／２９．５／１．５）、（４２．５／２６．５／３０．０／１．０）、（４２．５／２７．０／２８．５／２．０）、（４２．５／２７．０／２９．０／１．５）、（４２．５／２７．０／２９．５／１．０）、（４２．５／２７．５／２８．０／２．０）、（４２．５／２７．５／２８．５／１．５）、（４２．５／２７．５／２９．０／１．０）、（４２．５／２８．０／２７．５／２．０）、（４２．５／２８．０／２８．０／１．５）、（４２．５／２８．０／２８．５／１．０）、（４２．５／２８．５／２７．０／２．０）、（４２．５／２８．５／２７．５／１．５）、（４２．５／２８．５／２８．０／１．０）、（４２．５／２９．０／２６．５／２．０）、（４２．５／２９．０／２７．０／１．５）、（４２．５／２９．０／２７．５／１．０）、（４２．５／２９．５／２６．０／２．０）、（４２．５／２９．５／２６．５／１．５）、（４２．５／２９．５／２７．０／１．０）、（４２．５／３０．０／２５．５／２．０）、（４２．５／３０．０／２６．０／１．５）、（４２．５／３０．０／２６．５／１．０）、（４２．５／３０．５／２５．０／２．０）、（４２．５／３０．５／２５．５／１．５）、（４２．５／３０．５／２６．０／１．０）、（４２．５／３１．０／２４．５／２．０）、（４２．５／３１．０／２５．０／１．５）、（４２．５／３１．０／２５．５／１．０）、（４２．５／３１．５／２４．０／２．０）、（４２．５／３１．５／２４．５／１．５）、（４２．５／３１．５／２５．０／１．０）、（４２．５／３２．０／２３．５／２．０）、（４２．５／３２．０／２４．０／１．５）、（４２．５／３２．０／２４．５／１．０）、（４２．５／３２．５／２３．０／２．０）、（４２．５／３２．５／２３．５／１．５）、（４２．５／３２．５／２４．０／１．０）、（４２．５／３３．０／２２．５／２．０）、（４２．５／３３．０／２３．０／１．５）、（４２．５／３３．０／２３．５／１．０）、（４２．５／３３．５／２２．０／２．０）、（４２．５／３３．５／２２．５／１．５）、（４２．５／３３．５／２３．０／１．０）、（４２．５／３４．０／２１．５／２．０）、（４２．５／３４．０／２２．０／１．５）、（４２．５／３４．０／２２．５／１．０）、（４２．５／３４．５／２１．０／２．０）、（４２．５／３４．５／２１．５／１．５）、（４２．５／３４．５／２２．０／１．０）、（４２．５／３５．０／２０．５／２．０）、（４２．５／３５．０／２１．０／１．５）、（４２．５／３５．０／２１．５／１．０）、（４２．５／３５．５／２０．０／２．０）、（４２．５／３５．５／２０．５／１．５）、（４２．５／３５．５／２１．０／１．０）、（４２．５／３６．０／１９．５／２．０）、（４２．５／３６．０／２０．０／１．５）、（４２．５／３６．０／２０．５／１．０）、（４２．５／３６．５／１９．０／２．０）、（４２．５／３６．５／１９．５／１．５）、（４２．５／３６．５／２０．０／１．０）、（４２．５／３７．０／１８．５／２．０）、（４２．５／３７．０／１９．０／１．５）、（４２．５／３７．０／１９．５／１．０）、（４２．５／３７．５／１８．０／２．０）、（４２．５／３７．５／１８．５／１．５）、（４２．５／３７．５／１９．０／１．０）、（４２．５／３８．０／１７．５／２．０）、（４２．５／３８．０／１８．０／１．５）、（４２．５／３８．０／１８．５／１．０）、（４２．５／３８．５／１７．０／２．０）、（４２．５／３８．５／１７．５／１．５）、（４２．５／３８．５／１８．０／１．０）、（４２．５／３９．０／１６．５／２．０）、（４２．５／３９．０／１７．０／１．５）、（４２．５／３９．０／１７．５／１．０）、（４２．５／３９．５／１６．０／２．０）、（４２．５／３９．５／１６．５／１．５）、（４２．５／３９．５／１７．０／１．０）、（４２．５／４０．０／１５．５／２．０）、（４２．５／４０．０／１６．０／１．５）、（４２．５／４０．０／１６．５／１．０）、（４３．０／２５．０／３０．０／２．０）、（４３．０／２５．０／３０．５／１．５）、（４３．０／２５．０／３１．０／１．０）、（４３．０／２５．５／２９．５／２．０）、（４３．０／２５．５／３０．０／１．５）、（４３．０／２５．５／３０．５／１．０）、（４３．０／２６．０／２９．０／２．０）、（４３．０／２６．０／２９．５／１．５）、（４３．０／２６．０／３０．０／１．０）、（４３．０／２６．５／２８．５／２．０）、（４３．０／２６．５／２９．０／１．５）、（４３．０／２６．５／２９．５／１．０）、（４３．０／２７．０／２８．０／２．０）、（４３．０／２７．０／２８．５／１．５）、（４３．０／２７．０／２９．０／１．０）、（４３．０／２７．５／２７．５／２．０）、（４３．０／２７．５／２８．０／１．５）、（４３．０／２７．５／２８．５／１．０）、（４３．０／２８．０／２７．０／２．０）、（４３．０／２８．０／２７．５／１．５）、（４３．０／２８．０／２８．０／１．０）、（４３．０／２８．５／２６．５／２．０）、（４３．０／２８．５／２７．０／１．５）、（４３．０／２８．５／２７．５／１．０）、（４３．０／２９．０／２６．０／２．０）、（４３．０／２９．０／２６．５／１．５）、（４３．０／２９．０／２７．０／１．０）、（４３．０／２９．５／２５．５／２．０）、（４３．０／２９．５／２６．０／１．５）、（４３．０／２９．５／２６．５／１．０）、（４３．０／３０．０／２５．０／２．０）、（４３．０／３０．０／２５．５／１．５）、（４３．０／３０．０／２６．０／１．０）、（４３．０／３０．５／２４．５／２．０）、（４３．０／３０．５／２５．０／１．５）、（４３．０／３０．５／２５．５／１．０）、（４３．０／３１．０／２４．０／２．０）、（４３．０／３１．０／２４．５／１．５）、（４３．０／３１．０／２５．０／１．０）、（４３．０／３１．５／２３．５／２．０）、（４３．０／３１．５／２４．０／１．５）、（４３．０／３１．５／２４．５／１．０）、（４３．０／３２．０／２３．０／２．０）、（４３．０／３２．０／２３．５／１．５）、（４３．０／３２．０／２４．０／１．０）、（４３．０／３２．５／２２．５／２．０）、（４３．０／３２．５／２３．０／１．５）、（４３．０／３２．５／２３．５／１．０）、（４３．０／３３．０／２２．０／２．０）、（４３．０／３３．０／２２．５／１．５）、（４３．０／３３．０／２３．０／１．０）、（４３．０／３３．５／２１．５／２．０）、（４３．０／３３．５／２２．０／１．５）、（４３．０／３３．５／２２．５／１．０）、（４３．０／３４．０／２１．０／２．０）、（４３．０／３４．０／２１．５／１．５）、（４ ３．０／３４．０／２２．０／１．０）、（４３．０／３４．５／２０．５／２．０）、（４３．０／３４．５／２１．０／１．５）、（４３．０／３４．５／２１．５／１．０）、（４３．０／３５．０／２０．０／２．０）、（４３．０／３５．０／２０．５／１．５）、（４３．０／３５．０／２１．０／１．０）、（４３．０／３５．５／１９．５／２．０）、（４３．０／３５．５／２０．０／１．５）、（４３．０／３５．５／２０．５／１．０）、（４３．０／３６．０／１９．０／２．０）、（４３．０／３６．０／１９．５／１．５）、（４３．０／３６．０／２０．０／１．０）、（４３．０／３６．５／１８．５／２．０）、（４３．０／３６．５／１９．０／１．５）、（４３．０／３６．５／１９．５／１．０）、（４３．０／３７．０／１８．０／２．０）、（４３．０／３７．０／１８．５／１．５）、（４３．０／３７．０／１９．０／１．０）、（４３．０／３７．５／１７．５／２．０）、（４３．０／３７．５／１８．０／１．５）、（４３．０／３７．５／１８．５／１．０）、（４３．０／３８．０／１７．０／２．０）、（４３．０／３８．０／１７．５／１．５）、（４３．０／３８．０／１８．０／１．０）、（４３．０／３８．５／１６．５／２．０）、（４３．０／３８．５／１７．０／１．５）、（４３．０／３８．５／１７．５／１．０）、（４３．０／３９．０／１６．０／２．０）、（４３．０／３９．０／１６．５／１．５）、（４３．０／３９．０／１７．０／１．０）、（４３．０／３９．５／１５．５／２．０）、（４３．０／３９．５／１６．０／１．５）、（４３．０／３９．５／１６．５／１．０）、（４３．０／４０．０／１５．０／２．０）、（４３．０／４０．０／１５．５／１．５）、（４３．０／４０．０／１６．０／１．０）、（４３．５／２５．０／２９．５／２．０）、（４３．５／２５．０／３０．０／１．５）、（４３．５／２５．０／３０．５／１．０）、（４３．５／２５．５／２９．０／２．０）、（４３．５／２５．５／２９．５／１．５）、（４３．５／２５．５／３０．０／１．０）、（４３．５／２６．０／２８．５／２．０）、（４３．５／２６．０／２９．０／１．５）、（４３．５／２６．０／２９．５／１．０）、（４３．５／２６．５／２８．０／２．０）、（４３．５／２６．５／２８．５／１．５）、（４３．５／２６．５／２９．０／１．０）、（４３．５／２７．０／２７．５／２．０）、（４３．５／２７．０／２８．０／１．５）、（４３．５／２７．０／２８．５／１．０）、（４３．５／２７．５／２７．０／２．０）、（４３．５／２７．５／２７．５／１．５）、（４３．５／２７．５／２８．０／１．０）、（４３．５／２８．０／２６．５／２．０）、（４３．５／２８．０／２７．０／１．５）、（４３．５／２８．０／２７．５／１．０）、（４３．５／２８．５／２６．０／２．０）、（４３．５／２８．５／２６．５／１．５）、（４３．５／２８．５／２７．０／１．０）、（４３．５／２９．０／２５．５／２．０）、（４３．５／２９．０／２６．０／１．５）、（４３．５／２９．０／２６．５／１．０）、（４３．５／２９．５／２５．０／２．０）、（４３．５／２９．５／２５．５／１．５）、（４３．５／２９．５／２６．０／１．０）、（４３．５／３０．０／２４．５／２．０）、（４３．５／３０．０／２５．０／１．５）、（４３．５／３０．０／２５．５／１．０）、（４３．５／３０．５／２４．０／２．０）、（４３．５／３０．５／２４．５／１．５）、（４３．５／３０．５／２５．０／１．０）、（４３．５／３１．０／２３．５／２．０）、（４３．５／３１．０／２４．０／１．５）、（４３．５／３１．０／２４．５／１．０）、（４３．５／３１．５／２３．０／２．０）、（４３．５／３１．５／２３．５／１．５）、（４３．５／３１．５／２４．０／１．０）、（４３．５／３２．０／２２．５／２．０）、（４３．５／３２．０／２３．０／１．５）、（４３．５／３２．０／２３．５／１．０）、（４３．５／３２．５／２２．０／２．０）、（４３．５／３２．５／２２．５／１．５）、（４３．５／３２．５／２３．０／１．０）、（４３．５／３３．０／２１．５／２．０）、（４３．５／３３．０／２２．０／１．５）、（４３．５／３３．０／２２．５／１．０）、（４３．５／３３．５／２１．０／２．０）、（４３．５／３３．５／２１．５／１．５）、（４３．５／３３．５／２２．０／１．０）、（４３．５／３４．０／２０．５／２．０）、（４３．５／３４．０／２１．０／１．５）、（４３．５／３４．０／２１．５／１．０）、（４３．５／３４．５／２０．０／２．０）、（４３．５／３４．５／２０．５／１．５）、（４３．５／３４．５／２１．０／１．０）、（４３．５／３５．０／１９．５／２．０）、（４３．５／３５．０／２０．０／１．５）、（４３．５／３５．０／２０．５／１．０）、（４３．５／３５．５／１９．０／２．０）、（４３．５／３５．５／１９．５／１．５）、（４３．５／３５．５／２０．０／１．０）、（４３．５／３６．０／１８．５／２．０）、（４３．５／３６．０／１９．０／１．５）、（４３．５／３６．０／１９．５／１．０）、（４３．５／３６．５／１８．０／２．０）、（４３．５／３６．５／１８．５／１．５）、（４３．５／３６．５／１９．０／１．０）、（４３．５／３７．０／１７．５／２．０）、（４３．５／３７．０／１８．０／１．５）、（４３．５／３７．０／１８．５／１．０）、（４３．５／３７．５／１７．０／２．０）、（４３．５／３７．５／１７．５／１．５）、（４３．５／３７．５／１８．０／１．０）、（４３．５／３８．０／１６．５／２．０）、（４３．５／３８．０／１７．０／１．５）、（４３．５／３８．０／１７．５／１．０）、（４３．５／３８．５／１６．０／２．０）、（４３．５／３８．５／１６．５／１．５）、（４３．５／３８．５／１７．０／１．０）、（４３．５／３９．０／１５．５／２．０）、（４３．５／３９．０／１６．０／１．５）、（４３．５／３９．０／１６．５／１．０）、（４３．５／３９．５／１５．０／２．０）、（４３．５／３９．５／１５．５／１．５）、（４３．５／３９．５／１６．０／１．０）、（４３．５／４０．０／１５．０／１．５）、（４３．５／４０．０／１５．５／１．０）、（４４．０／２５．０／２９．０／２．０）、（４４．０／２５．０／２９．５／１．５）、（４４．０／２５．０／３０．０／１．０）、（４４．０／２５．５／２８．５／２．０）、（４４．０／２５．５／２９．０／１．５）、（４４．０／２５．５／２９．５／１．０）、（４４．０／２６．０／２８．０／２．０）、（４４．０／２６．０／２８．５／１．５）、（４４．０／２６．０／２９．０／１．０）、（４４．０／２６．５／２７．５／２．０）、（４４．０／２６．５／２８．０／１．５）、（４４．０／２６．５／２８．５／１．０）、（４４．０／２７．０／２７．０／２．０）、（４４．０／２７．０／２７．５／１．５）、（４４．０／２７．０／２８．０／１．０）、（４４．０／２７．５／２６．５／２．０）、（４４．０／２７．５／２７．０／１．５）、（４４．０／２７．５／２７．５／１．０）、（４４．０／２８．０／２６．０／２．０）、（４４．０／２８．０／２６．５／１．５）、（４４．０／２８．０／２７．０／１．０）、（４４．０／２８．５／２５．５／２．０）、（４４．０／２８．５／２６．０／１．５）、（４４．０／２８．５／２６．５／１．０）、（４４．０／２９．０／２５．０／２．０）、（４４．０／２９．０／２５．５／１．５）、（４４．０／２９．０／２６．０／１．０）、（４４．０／２９．５／２４．５／２．０）、（４４．０／２９．５／２５．０／１．５）、（４４．０／２９．５／２５．５／１．０）、（４４．０／３０．０／２４．０／２．０）、（４４．０／３０．０／２４．５／１．５）、（４４．０／３０．０／２５．０／１．０）、（４４．０／３０．５／２３．５／２．０）、（４４．０／３０．５／２４．０／１．５）、（４４．０／３０．５／２４．５／１．０）、（４４．０／３１．０／２３．０／２．０）、（４４．０／３１．０／２３．５／１．５）、（４４．０／３１．０／２４．０／１．０）、（４４．０／３１．５／２２．５／２．０）、（４４．０／３１．５／２３．０／１．５）、（４４．０／３１．５／２３．５／１．０）、（４４．０／３２．０／２２．０／２．０）、（４４．０／３２．０／２２．５／１．５）、（４４．０／３２．０／２３．０／１．０）、（４４．０／３２．５／２１．５／２．０）、（４４．０／３２．５／２２．０／１．５）、（４４．０／３２．５／２２．５／１．０）、（４４．０／３３．０／２１．０／２．０）、（４４．０／３３．０／２１．５／１．５）、（４４．０／３３．０／２２．０／１．０）、（４４．０／３３．５／２０．５／２．０）、（４４．０／３３．５／２１．０／１．５）、（４４．０／３３．５／２１．５／１．０）、（４４．０／３４．０／２０．０／２．０）、（４４．０／３４．０／２０．５／１．５）、（４４．０／３４．０／２１．０／１．０）、（４４．０／３４．５／１９．５／２．０）、（４４．０／３４．５／２０．０／１．５）、（４４．０／３４．５／２０．５／１．０）、（４４．０／３５．０／１９．０／２．０）、（４４．０／３５．０／１９．５／１．５）、（４４．０／３５．０／２０．０／１．０）、（４４．０／３５．５／１８．５／２．０）、（４４．０／３５．５／１９．０／１．５）、（４４．０／３５．５／１９．５／１．０）、（４４．０／３６．０／１８．０／２．０）、（４４．０／３６．０／１８．５／１．５）、（４４．０／３６．０／１９．０／１．０）、（４４．０／３６．５／１７．５／２．０）、（４４．０／３６．５／１８．０／１．５）、（４４．０／３６．５／１８．５／１．０）、（４４．０／３７．０／１７．０／２．０）、（４４．０／３７．０／１７．５／１．５）、（４４．０／３７．０／１８．０／１．０）、（４４．０／３７．５／１６．５／２．０）、（４４．０／３７．５／１７．０／１．５）、（４４．０／３７．５／１７．５／１．０）、（４４．０／３８．０／１６．０／２．０）、（４４．０／３８．０／１６．５／１．５）、（４４．０／３８．０／１７．０／１．０）、（４４．０／３８．５／１５．５／２．０）、（４４．０／３８．５／１６．０／１．５）、（４４．０／３８．５／１６．５／１．０）、（４４．０／３９．０／１５．０／２．０）、（４４．０／３９．０／１５．５／１．５）、（４４．０／３９．０／１６．０／１．０）、（４４．０／３９．５／１５．０／１．５）、（４４．０／３９．５／１５．５／１．０）、（４４．０／４０．０／１５．０／１．０）、（４４．５／２５．０／２８．５／２．０）、（４４．５／２５．０／２９．０／１．５）、（４４．５／２５．０／２９．５／１．０）、（４４．５／２５．５／２８．０／２．０）、（４４．５／２５．５／２８．５／１．５）、（４４．５／２５．５／２９．０／１．０）、（４４．５／２６．０／２７．５／２．０）、（４４．５／２６．０／２８．０／１．５）、（４４．５／２６．０／２８．５／１．０）、（４４．５／２６．５／２７．０／２．０）、（４４．５／２６．５／２７．５／１．５）、（４４．５／２６．５／２８．０／１．０）、（４４．５／２７．０／２６．５／２．０）、（４４．５／２７．０／２７．０／１．５）、（４４．５／２７．０／２７．５／１．０）、（４４．５／２７．５／２６．０／２．０）、（４４．５／２７．５／２６．５／１．５）、（４４．５／２７．５／２７．０／１．０）、（４４．５／２８．０／２５．５／２．０）、（４４．５／２８．０／２６．０／１．５）、（４４．５／２８．０／２６．５／１．０）、（４４．５／２８．５／２５．０／２．０）、（４４．５／２８．５／２５．５／１．５）、（４４．５／２８．５／２６．０／１．０）、（４４．５／２９．０／２４．５／２．０） 、（４４．５／２９．０／２５．０／１．５）、（４４．５／２９．０／２５．５／１．０）、（４４．５／２９．５／２４．０／２．０）、（４４．５／２９．５／２４．５／１．５）、（４４．５／２９．５／２５．０／１．０）、（４４．５／３０．０／２３．５／２．０）、（４４．５／３０．０／２４．０／１．５）、（４４．５／３０．０／２４．５／１．０）、（４４．５／３０．５／２３．０／２．０）、（４４．５／３０．５／２３．５／１．５）、（４４．５／３０．５／２４．０／１．０）、（４４．５／３１．０／２２．５／２．０）、（４４．５／３１．０／２３．０／１．５）、（４４．５／３１．０／２３．５／１．０）、（４４．５／３１．５／２２．０／２．０）、（４４．５／３１．５／２２．５／１．５）、（４４．５／３１．５／２３．０／１．０）、（４４．５／３２．０／２１．５／２．０）、（４４．５／３２．０／２２．０／１．５）、（４４．５／３２．０／２２．５／１．０）、（４４．５／３２．５／２１．０／２．０）、（４４．５／３２．５／２１．５／１．５）、（４４．５／３２．５／２２．０／１．０）、（４４．５／３３．０／２０．５／２．０）、（４４．５／３３．０／２１．０／１．５）、（４４．５／３３．０／２１．５／１．０）、（４４．５／３３．５／２０．０／２．０）、（４４．５／３３．５／２０．５／１．５）、（４４．５／３３．５／２１．０／１．０）、（４４．５／３４．０／１９．５／２．０）、（４４．５／３４．０／２０．０／１．５）、（４４．５／３４．０／２０．５／１．０）、（４４．５／３４．５／１９．０／２．０）、（４４．５／３４．５／１９．５／１．５）、（４４．５／３４．５／２０．０／１．０）、（４４．５／３５．０／１８．５／２．０）、（４４．５／３５．０／１９．０／１．５）、（４４．５／３５．０／１９．５／１．０）、（４４．５／３５．５／１８．０／２．０）、（４４．５／３５．５／１８．５／１．５）、（４４．５／３５．５／１９．０／１．０）、（４４．５／３６．０／１７．５／２．０）、（４４．５／３６．０／１８．０／１．５）、（４４．５／３６．０／１８．５／１．０）、（４４．５／３６．５／１７．０／２．０）、（４４．５／３６．５／１７．５／１．５）、（４４．５／３６．５／１８．０／１．０）、（４４．５／３７．０／１６．５／２．０）、（４４．５／３７．０／１７．０／１．５）、（４４．５／３７．０／１７．５／１．０）、（４４．５／３７．５／１６．０／２．０）、（４４．５／３７．５／１６．５／１．５）、（４４．５／３７．５／１７．０／１．０）、（４４．５／３８．０／１５．５／２．０）、（４４．５／３８．０／１６．０／１．５）、（４４．５／３８．０／１６．５／１．０）、（４４．５／３８．５／１５．０／２．０）、（４４．５／３８．５／１５．５／１．５）、（４４．５／３８．５／１６．０／１．０）、（４４．５／３９．０／１５．０／１．５）、（４４．５／３９．０／１５．５／１．０）、（４４．５／３９．５／１５．０／１．０）、（４５．０／２５．０／２８．０／２．０）、（４５．０／２５．０／２８．５／１．５）、（４５．０／２５．０／２９．０／１．０）、（４５．０／２５．５／２７．５／２．０）、（４５．０／２５．５／２８．０／１．５）、（４５．０／２５．５／２８．５／１．０）、（４５．０／２６．０／２７．０／２．０）、（４５．０／２６．０／２７．５／１．５）、（４５．０／２６．０／２８．０／１．０）、（４５．０／２６．５／２６．５／２．０）、（４５．０／２６．５／２７．０／１．５）、（４５．０／２６．５／２７．５／１．０）、（４５．０／２７．０／２６．０／２．０）、（４５．０／２７．０／２６．５／１．５）、（４５．０／２７．０／２７．０／１．０）、（４５．０／２７．５／２５．５／２．０）、（４５．０／２７．５／２６．０／１．５）、（４５．０／２７．５／２６．５／１．０）、（４５．０／２８．０／２５．０／２．０）、（４５．０／２８．０／２５．５／１．５）、（４５．０／２８．０／２６．０／１．０）、（４５．０／２８．５／２４．５／２．０）、（４５．０／２８．５／２５．０／１．５）、（４５．０／２８．５／２５．５／１．０）、（４５．０／２９．０／２４．０／２．０）、（４５．０／２９．０／２４．５／１．５）、（４５．０／２９．０／２５．０／１．０）、（４５．０／２９．５／２３．５／２．０）、（４５．０／２９．５／２４．０／１．５）、（４５．０／２９．５／２４．５／１．０）、（４５．０／３０．０／２３．０／２．０）、（４５．０／３０．０／２３．５／１．５）、（４５．０／３０．０／２４．０／１．０）、（４５．０／３０．５／２２．５／２．０）、（４５．０／３０．５／２３．０／１．５）、（４５．０／３０．５／２３．５／１．０）、（４５．０／３１．０／２２．０／２．０）、（４５．０／３１．０／２２．５／１．５）、（４５．０／３１．０／２３．０／１．０）、（４５．０／３１．５／２１．５／２．０）、（４５．０／３１．５／２２．０／１．５）、（４５．０／３１．５／２２．５／１．０）、（４５．０／３２．０／２１．０／２．０）、（４５．０／３２．０／２１．５／１．５）、（４５．０／３２．０／２２．０／１．０）、（４５．０／３２．５／２０．５／２．０）、（４５．０／３２．５／２１．０／１．５）、（４５．０／３２．５／２１．５／１．０）、（４５．０／３３．０／２０．０／２．０）、（４５．０／３３．０／２０．５／１．５）、（４５．０／３３．０／２１．０／１．０）、（４５．０／３３．５／１９．５／２．０）、（４５．０／３３．５／２０．０／１．５）、（４５．０／３３．５／２０．５／１．０）、（４５．０／３４．０／１９．０／２．０）、（４５．０／３４．０／１９．５／１．５）、（４５．０／３４．０／２０．０／１．０）、（４５．０／３４．５／１８．５／２．０）、（４５．０／３４．５／１９．０／１．５）、（４５．０／３４．５／１９．５／１．０）、（４５．０／３５．０／１８．０／２．０）、（４５．０／３５．０／１８．５／１．５）、（４５．０／３５．０／１９．０／１．０）、（４５．０／３５．５／１７．５／２．０）、（４５．０／３５．５／１８．０／１．５）、（４５．０／３５．５／１８．５／１．０）、（４５．０／３６．０／１７．０／２．０）、（４５．０／３６．０／１７．５／１．５）、（４５．０／３６．０／１８．０／１．０）、（４５．０／３６．５／１６．５／２．０）、（４５．０／３６．５／１７．０／１．５）、（４５．０／３６．５／１７．５／１．０）、（４５．０／３７．０／１６．０／２．０）、（４５．０／３７．０／１６．５／１．５）、（４５．０／３７．０／１７．０／１．０）、（４５．０／３７．５／１５．５／２．０）、（４５．０／３７．５／１６．０／１．５）、（４５．０／３７．５／１６．５／１．０）、（４５．０／３８．０／１５．０／２．０）、（４５．０／３８．０／１５．５／１．５）、（４５．０／３８．０／１６．０／１．０）、（４５．０／３８．５／１５．０／１．５）、（４５．０／３８．５／１５．５／１．０）、（４５．０／３９．０／１５．０／１．０）、（４５．５／２５．０／２７．５／２．０）、（４５．５／２５．０／２８．０／１．５）、（４５．５／２５．０／２８．５／１．０）、（４５．５／２５．５／２７．０／２．０）、（４５．５／２５．５／２７．５／１．５）、（４５．５／２５．５／２８．０／１．０）、（４５．５／２６．０／２６．５／２．０）、（４５．５／２６．０／２７．０／１．５）、（４５．５／２６．０／２７．５／１．０）、（４５．５／２６．５／２６．０／２．０）、（４５．５／２６．５／２６．５／１．５）、（４５．５／２６．５／２７．０／１．０）、（４５．５／２７．０／２５．５／２．０）、（４５．５／２７．０／２６．０／１．５）、（４５．５／２７．０／２６．５／１．０）、（４５．５／２７．５／２５．０／２．０）、（４５．５／２７．５／２５．５／１．５）、（４５．５／２７．５／２６．０／１．０）、（４５．５／２８．０／２４．５／２．０）、（４５．５／２８．０／２５．０／１．５）、（４５．５／２８．０／２５．５／１．０）、（４５．５／２８．５／２４．０／２．０）、（４５．５／２８．５／２４．５／１．５）、（４５．５／２８．５／２５．０／１．０）、（４５．５／２９．０／２３．５／２．０）、（４５．５／２９．０／２４．０／１．５）、（４５．５／２９．０／２４．５／１．０）、（４５．５／２９．５／２３．０／２．０）、（４５．５／２９．５／２３．５／１．５）、（４５．５／２９．５／２４．０／１．０）、（４５．５／３０．０／２２．５／２．０）、（４５．５／３０．０／２３．０／１．５）、（４５．５／３０．０／２３．５／１．０）、（４５．５／３０．５／２２．０／２．０）、（４５．５／３０．５／２２．５／１．５）、（４５．５／３０．５／２３．０／１．０）、（４５．５／３１．０／２１．５／２．０）、（４５．５／３１．０／２２．０／１．５）、（４５．５／３１．０／２２．５／１．０）、（４５．５／３１．５／２１．０／２．０）、（４５．５／３１．５／２１．５／１．５）、（４５．５／３１．５／２２．０／１．０）、（４５．５／３２．０／２０．５／２．０）、（４５．５／３２．０／２１．０／１．５）、（４５．５／３２．０／２１．５／１．０）、（４５．５／３２．５／２０．０／２．０）、（４５．５／３２．５／２０．５／１．５）、（４５．５／３２．５／２１．０／１．０）、（４５．５／３３．０／１９．５／２．０）、（４５．５／３３．０／２０．０／１．５）、（４５．５／３３．０／２０．５／１．０）、（４５．５／３３．５／１９．０／２．０）、（４５．５／３３．５／１９．５／１．５）、（４５．５／３３．５／２０．０／１．０）、（４５．５／３４．０／１８．５／２．０）、（４５．５／３４．０／１９．０／１．５）、（４５．５／３４．０／１９．５／１．０）、（４５．５／３４．５／１８．０／２．０）、（４５．５／３４．５／１８．５／１．５）、（４５．５／３４．５／１９．０／１．０）、（４５．５／３５．０／１７．５／２．０）、（４５．５／３５．０／１８．０／１．５）、（４５．５／３５．０／１８．５／１．０）、（４５．５／３５．５／１７．０／２．０）、（４５．５／３５．５／１７．５／１．５）、（４５．５／３５．５／１８．０／１．０）、（４５．５／３６．０／１６．５／２．０）、（４５．５／３６．０／１７．０／１．５）、（４５．５／３６．０／１７．５／１．０）、（４５．５／３６．５／１６．０／２．０）、（４５．５／３６．５／１６．５／１．５）、（４５．５／３６．５／１７．０／１．０）、（４５．５／３７．０／１５．５／２．０）、（４５．５／３７．０／１６．０／１．５）、（４５．５／３７．０／１６．５／１．０）、（４５．５／３７．５／１５．０／２．０）、（４５．５／３７．５／１５．５／１．５）、（４５．５／３７．５／１６．０／１．０）、（４５．５／３８．０／１５．０／１．５）、（４５．５／３８．０／１５．５／１．０）、（４５．５／３８．５／１５．０／１．０）、（４６．０／２５．０／２７．０／２．０）、（４６．０／２５．０／２７．５／１．５）、（４６．０／２５．０／２８．０／１．０）、（４６．０／２５．５／２６．５／２．０）、（４６．０／２５．５／２７．０／１．５）、（４６．０／２５．５／２７．５／１．０）、（４６．０／２６．０／２６．０／２．０）、（４６．０／２６．０／２６．５／１．５）、（４６．０／２６．０／２７．０／１．０）、（４６．０／２６．５／２５．５／２．０）、（４６．０／２６．５／２６．０／１．５）、（４６．０／２６．５／２６．５／１．０）、（４６．０／２７．０／２５．０／２．０）、（４６．０／２７．０／２５．５／１．５）、（４６．０／２７．０／２６．０／１．０）、（４６．０／２７．５／２４．５／２．０）、（４６．０／２７．５／２５．０／１ ．５）、（４６．０／２７．５／２５．５／１．０）、（４６．０／２８．０／２４．０／２．０）、（４６．０／２８．０／２４．５／１．５）、（４６．０／２８．０／２５．０／１．０）、（４６．０／２８．５／２３．５／２．０）、（４６．０／２８．５／２４．０／１．５）、（４６．０／２８．５／２４．５／１．０）、（４６．０／２９．０／２３．０／２．０）、（４６．０／２９．０／２３．５／１．５）、（４６．０／２９．０／２４．０／１．０）、（４６．０／２９．５／２２．５／２．０）、（４６．０／２９．５／２３．０／１．５）、（４６．０／２９．５／２３．５／１．０）、（４６．０／３０．０／２２．０／２．０）、（４６．０／３０．０／２２．５／１．５）、（４６．０／３０．０／２３．０／１．０）、（４６．０／３０．５／２１．５／２．０）、（４６．０／３０．５／２２．０／１．５）、（４６．０／３０．５／２２．５／１．０）、（４６．０／３１．０／２１．０／２．０）、（４６．０／３１．０／２１．５／１．５）、（４６．０／３１．０／２２．０／１．０）、（４６．０／３１．５／２０．５／２．０）、（４６．０／３１．５／２１．０／１．５）、（４６．０／３１．５／２１．５／１．０）、（４６．０／３２．０／２０．０／２．０）、（４６．０／３２．０／２０．５／１．５）、（４６．０／３２．０／２１．０／１．０）、（４６．０／３２．５／１９．５／２．０）、（４６．０／３２．５／２０．０／１．５）、（４６．０／３２．５／２０．５／１．０）、（４６．０／３３．０／１９．０／２．０）、（４６．０／３３．０／１９．５／１．５）、（４６．０／３３．０／２０．０／１．０）、（４６．０／３３．５／１８．５／２．０）、（４６．０／３３．５／１９．０／１．５）、（４６．０／３３．５／１９．５／１．０）、（４６．０／３４．０／１８．０／２．０）、（４６．０／３４．０／１８．５／１．５）、（４６．０／３４．０／１９．０／１．０）、（４６．０／３４．５／１７．５／２．０）、（４６．０／３４．５／１８．０／１．５）、（４６．０／３４．５／１８．５／１．０）、（４６．０／３５．０／１７．０／２．０）、（４６．０／３５．０／１７．５／１．５）、（４６．０／３５．０／１８．０／１．０）、（４６．０／３５．５／１６．５／２．０）、（４６．０／３５．５／１７．０／１．５）、（４６．０／３５．５／１７．５／１．０）、（４６．０／３６．０／１６．０／２．０）、（４６．０／３６．０／１６．５／１．５）、（４６．０／３６．０／１７．０／１．０）、（４６．０／３６．５／１５．５／２．０）、（４６．０／３６．５／１６．０／１．５）、（４６．０／３６．５／１６．５／１．０）、（４６．０／３７．０／１５．０／２．０）、（４６．０／３７．０／１５．５／１．５）、（４６．０／３７．０／１６．０／１．０）、（４６．０／３７．５／１５．０／１．５）、（４６．０／３７．５／１５．５／１．０）、（４６．０／３８．０／１５．０／１．０）、（４６．５／２５．０／２６．５／２．０）、（４６．５／２５．０／２７．０／１．５）、（４６．５／２５．０／２７．５／１．０）、（４６．５／２５．５／２６．０／２．０）、（４６．５／２５．５／２６．５／１．５）、（４６．５／２５．５／２７．０／１．０）、（４６．５／２６．０／２５．５／２．０）、（４６．５／２６．０／２６．０／１．５）、（４６．５／２６．０／２６．５／１．０）、（４６．５／２６．５／２５．０／２．０）、（４６．５／２６．５／２５．５／１．５）、（４６．５／２６．５／２６．０／１．０）、（４６．５／２７．０／２４．５／２．０）、（４６．５／２７．０／２５．０／１．５）、（４６．５／２７．０／２５．５／１．０）、（４６．５／２７．５／２４．０／２．０）、（４６．５／２７．５／２４．５／１．５）、（４６．５／２７．５／２５．０／１．０）、（４６．５／２８．０／２３．５／２．０）、（４６．５／２８．０／２４．０／１．５）、（４６．５／２８．０／２４．５／１．０）、（４６．５／２８．５／２３．０／２．０）、（４６．５／２８．５／２３．５／１．５）、（４６．５／２８．５／２４．０／１．０）、（４６．５／２９．０／２２．５／２．０）、（４６．５／２９．０／２３．０／１．５）、（４６．５／２９．０／２３．５／１．０）、（４６．５／２９．５／２２．０／２．０）、（４６．５／２９．５／２２．５／１．５）、（４６．５／２９．５／２３．０／１．０）、（４６．５／３０．０／２１．５／２．０）、（４６．５／３０．０／２２．０／１．５）、（４６．５／３０．０／２２．５／１．０）、（４６．５／３０．５／２１．０／２．０）、（４６．５／３０．５／２１．５／１．５）、（４６．５／３０．５／２２．０／１．０）、（４６．５／３１．０／２０．５／２．０）、（４６．５／３１．０／２１．０／１．５）、（４６．５／３１．０／２１．５／１．０）、（４６．５／３１．５／２０．０／２．０）、（４６．５／３１．５／２０．５／１．５）、（４６．５／３１．５／２１．０／１．０）、（４６．５／３２．０／１９．５／２．０）、（４６．５／３２．０／２０．０／１．５）、（４６．５／３２．０／２０．５／１．０）、（４６．５／３２．５／１９．０／２．０）、（４６．５／３２．５／１９．５／１．５）、（４６．５／３２．５／２０．０／１．０）、（４６．５／３３．０／１８．５／２．０）、（４６．５／３３．０／１９．０／１．５）、（４６．５／３３．０／１９．５／１．０）、（４６．５／３３．５／１８．０／２．０）、（４６．５／３３．５／１８．５／１．５）、（４６．５／３３．５／１９．０／１．０）、（４６．５／３４．０／１７．５／２．０）、（４６．５／３４．０／１８．０／１．５）、（４６．５／３４．０／１８．５／１．０）、（４６．５／３４．５／１７．０／２．０）、（４６．５／３４．５／１７．５／１．５）、（４６．５／３４．５／１８．０／１．０）、（４６．５／３５．０／１６．５／２．０）、（４６．５／３５．０／１７．０／１．５）、（４６．５／３５．０／１７．５／１．０）、（４６．５／３５．５／１６．０／２．０）、（４６．５／３５．５／１６．５／１．５）、（４６．５／３５．５／１７．０／１．０）、（４６．５／３６．０／１５．５／２．０）、（４６．５／３６．０／１６．０／１．５）、（４６．５／３６．０／１６．５／１．０）、（４６．５／３６．５／１５．０／２．０）、（４６．５／３６．５／１５．５／１．５）、（４６．５／３６．５／１６．０／１．０）、（４６．５／３７．０／１５．０／１．５）、（４６．５／３７．０／１５．５／１．０）、（４６．５／３７．５／１５．０／１．０）、（４７．０／２５．０／２６．０／２．０）、（４７．０／２５．０／２６．５／１．５）、（４７．０／２５．０／２７．０／１．０）、（４７．０／２５．５／２５．５／２．０）、（４７．０／２５．５／２６．０／１．５）、（４７．０／２５．５／２６．５／１．０）、（４７．０／２６．０／２５．０／２．０）、（４７．０／２６．０／２５．５／１．５）、（４７．０／２６．０／２６．０／１．０）、（４７．０／２６．５／２４．５／２．０）、（４７．０／２６．５／２５．０／１．５）、（４７．０／２６．５／２５．５／１．０）、（４７．０／２７．０／２４．０／２．０）、（４７．０／２７．０／２４．５／１．５）、（４７．０／２７．０／２５．０／１．０）、（４７．０／２７．５／２３．５／２．０）、（４７．０／２７．５／２４．０／１．５）、（４７．０／２７．５／２４．５／１．０）、（４７．０／２８．０／２３．０／２．０）、（４７．０／２８．０／２３．５／１．５）、（４７．０／２８．０／２４．０／１．０）、（４７．０／２８．５／２２．５／２．０）、（４７．０／２８．５／２３．０／１．５）、（４７．０／２８．５／２３．５／１．０）、（４７．０／２９．０／２２．０／２．０）、（４７．０／２９．０／２２．５／１．５）、（４７．０／２９．０／２３．０／１．０）、（４７．０／２９．５／２１．５／２．０）、（４７．０／２９．５／２２．０／１．５）、（４７．０／２９．５／２２．５／１．０）、（４７．０／３０．０／２１．０／２．０）、（４７．０／３０．０／２１．５／１．５）、（４７．０／３０．０／２２．０／１．０）、（４７．０／３０．５／２０．５／２．０）、（４７．０／３０．５／２１．０／１．５）、（４７．０／３０．５／２１．５／１．０）、（４７．０／３１．０／２０．０／２．０）、（４７．０／３１．０／２０．５／１．５）、（４７．０／３１．０／２１．０／１．０）、（４７．０／３１．５／１９．５／２．０）、（４７．０／３１．５／２０．０／１．５）、（４７．０／３１．５／２０．５／１．０）、（４７．０／３２．０／１９．０／２．０）、（４７．０／３２．０／１９．５／１．５）、（４７．０／３２．０／２０．０／１．０）、（４７．０／３２．５／１８．５／２．０）、（４７．０／３２．５／１９．０／１．５）、（４７．０／３２．５／１９．５／１．０）、（４７．０／３３．０／１８．０／２．０）、（４７．０／３３．０／１８．５／１．５）、（４７．０／３３．０／１９．０／１．０）、（４７．０／３３．５／１７．５／２．０）、（４７．０／３３．５／１８．０／１．５）、（４７．０／３３．５／１８．５／１．０）、（４７．０／３４．０／１７．０／２．０）、（４７．０／３４．０／１７．５／１．５）、（４７．０／３４．０／１８．０／１．０）、（４７．０／３４．５／１６．５／２．０）、（４７．０／３４．５／１７．０／１．５）、（４７．０／３４．５／１７．５／１．０）、（４７．０／３５．０／１６．０／２．０）、（４７．０／３５．０／１６．５／１．５）、（４７．０／３５．０／１７．０／１．０）、（４７．０／３５．５／１５．５／２．０）、（４７．０／３５．５／１６．０／１．５）、（４７．０／３５．５／１６．５／１．０）、（４７．０／３６．０／１５．０／２．０）、（４７．０／３６．０／１５．５／１．５）、（４７．０／３６．０／１６．０／１．０）、（４７．０／３６．５／１５．０／１．５）、（４７．０／３６．５／１５．５／１．０）、（４７．０／３７．０／１５．０／１．０）、（４７．５／２５．０／２５．５／２．０）、（４７．５／２５．０／２６．０／１．５）、（４７．５／２５．０／２６．５／１．０）、（４７．５／２５．５／２５．０／２．０）、（４７．５／２５．５／２５．５／１．５）、（４７．５／２５．５／２６．０／１．０）、（４７．５／２６．０／２４．５／２．０）、（４７．５／２６．０／２５．０／１．５）、（４７．５／２６．０／２５．５／１．０）、（４７．５／２６．５／２４．０／２．０）、（４７．５／２６．５／２４．５／１．５）、（４７．５／２６．５／２５．０／１．０）、（４７．５／２７．０／２３．５／２．０）、（４７．５／２７．０／２４．０／１．５）、（４７．５／２７．０／２４．５／１．０）、（４７．５／２７．５／２３．０／２．０）、（４７．５／２７．５／２３．５／１．５）、（４７．５／２７．５／２４．０／１．０）、（４７．５／２８．０／２２．５／２．０）、（４７．５／２８．０／２３．０／１．５）、（４７．５／２８．０／２３．５／１．０）、（４７．５／２８．５／２２．０／２．０）、（４７．５／２８．５／２２．５／１．５）、（４７．５／２８．５／２３．０／１．０）、（４７．５／２９．０／２１．５／２．０）、（４７．５／２９．０／２２．０／１．５）、（４７．５／２９．０／２２．５／１．０）、（４７．５／２９．５／２１．０／２．０）、（４７．５／２９．５／２１．５／１．５）、（４７．５／２９．５／２２．０／１．０）、（４７．５／３０．０／２０．５／２．０）、（４７．５／３０．０／２１．０／１．５）、（４７．５／３０．０／２１．５／１．０）、（４７．５／３０．５／２０．０／２．０）、（４７．５／３０．５／２０．５／１．５）、（４７．５／３０．５／２１． ０／１．０）、（４７．５／３１．０／１９．５／２．０）、（４７．５／３１．０／２０．０／１．５）、（４７．５／３１．０／２０．５／１．０）、（４７．５／３１．５／１９．０／２．０）、（４７．５／３１．５／１９．５／１．５）、（４７．５／３１．５／２０．０／１．０）、（４７．５／３２．０／１８．５／２．０）、（４７．５／３２．０／１９．０／１．５）、（４７．５／３２．０／１９．５／１．０）、（４７．５／３２．５／１８．０／２．０）、（４７．５／３２．５／１８．５／１．５）、（４７．５／３２．５／１９．０／１．０）、（４７．５／３３．０／１７．５／２．０）、（４７．５／３３．０／１８．０／１．５）、（４７．５／３３．０／１８．５／１．０）、（４７．５／３３．５／１７．０／２．０）、（４７．５／３３．５／１７．５／１．５）、（４７．５／３３．５／１８．０／１．０）、（４７．５／３４．０／１６．５／２．０）、（４７．５／３４．０／１７．０／１．５）、（４７．５／３４．０／１７．５／１．０）、（４７．５／３４．５／１６．０／２．０）、（４７．５／３４．５／１６．５／１．５）、（４７．５／３４．５／１７．０／１．０）、（４７．５／３５．０／１５．５／２．０）、（４７．５／３５．０／１６．０／１．５）、（４７．５／３５．０／１６．５／１．０）、（４７．５／３５．５／１５．０／２．０）、（４７．５／３５．５／１５．５／１．５）、（４７．５／３５．５／１６．０／１．０）、（４７．５／３６．０／１５．０／１．５）、（４７．５／３６．０／１５．５／１．０）、（４７．５／３６．５／１５．０／１．０）、（４８．０／２５．０／２５．０／２．０）、（４８．０／２５．０／２５．５／１．５）、（４８．０／２５．０／２６．０／１．０）、（４８．０／２５．５／２４．５／２．０）、（４８．０／２５．５／２５．０／１．５）、（４８．０／２５．５／２５．５／１．０）、（４８．０／２６．０／２４．０／２．０）、（４８．０／２６．０／２４．５／１．５）、（４８．０／２６．０／２５．０／１．０）、（４８．０／２６．５／２３．５／２．０）、（４８．０／２６．５／２４．０／１．５）、（４８．０／２６．５／２４．５／１．０）、（４８．０／２７．０／２３．０／２．０）、（４８．０／２７．０／２３．５／１．５）、（４８．０／２７．０／２４．０／１．０）、（４８．０／２７．５／２２．５／２．０）、（４８．０／２７．５／２３．０／１．５）、（４８．０／２７．５／２３．５／１．０）、（４８．０／２８．０／２２．０／２．０）、（４８．０／２８．０／２２．５／１．５）、（４８．０／２８．０／２３．０／１．０）、（４８．０／２８．５／２１．５／２．０）、（４８．０／２８．５／２２．０／１．５）、（４８．０／２８．５／２２．５／１．０）、（４８．０／２９．０／２１．０／２．０）、（４８．０／２９．０／２１．５／１．５）、（４８．０／２９．０／２２．０／１．０）、（４８．０／２９．５／２０．５／２．０）、（４８．０／２９．５／２１．０／１．５）、（４８．０／２９．５／２１．５／１．０）、（４８．０／３０．０／２０．０／２．０）、（４８．０／３０．０／２０．５／１．５）、（４８．０／３０．０／２１．０／１．０）、（４８．０／３０．５／１９．５／２．０）、（４８．０／３０．５／２０．０／１．５）、（４８．０／３０．５／２０．５／１．０）、（４８．０／３１．０／１９．０／２．０）、（４８．０／３１．０／１９．５／１．５）、（４８．０／３１．０／２０．０／１．０）、（４８．０／３１．５／１８．５／２．０）、（４８．０／３１．５／１９．０／１．５）、（４８．０／３１．５／１９．５／１．０）、（４８．０／３２．０／１８．０／２．０）、（４８．０／３２．０／１８．５／１．５）、（４８．０／３２．０／１９．０／１．０）、（４８．０／３２．５／１７．５／２．０）、（４８．０／３２．５／１８．０／１．５）、（４８．０／３２．５／１８．５／１．０）、（４８．０／３３．０／１７．０／２．０）、（４８．０／３３．０／１７．５／１．５）、（４８．０／３３．０／１８．０／１．０）、（４８．０／３３．５／１６．５／２．０）、（４８．０／３３．５／１７．０／１．５）、（４８．０／３３．５／１７．５／１．０）、（４８．０／３４．０／１６．０／２．０）、（４８．０／３４．０／１６．５／１．５）、（４８．０／３４．０／１７．０／１．０）、（４８．０／３４．５／１５．５／２．０）、（４８．０／３４．５／１６．０／１．５）、（４８．０／３４．５／１６．５／１．０）、（４８．０／３５．０／１５．０／２．０）、（４８．０／３５．０／１５．５／１．５）、（４８．０／３５．０／１６．０／１．０）、（４８．０／３５．５／１５．０／１．５）、（４８．０／３５．５／１５．５／１．０）、（４８．０／３６．０／１５．０／１．０）、（４８．５／２５．０／２４．５／２．０）、（４８．５／２５．０／２５．０／１．５）、（４８．５／２５．０／２５．５／１．０）、（４８．５／２５．５／２４．０／２．０）、（４８．５／２５．５／２４．５／１．５）、（４８．５／２５．５／２５．０／１．０）、（４８．５／２６．０／２３．５／２．０）、（４８．５／２６．０／２４．０／１．５）、（４８．５／２６．０／２４．５／１．０）、（４８．５／２６．５／２３．０／２．０）、（４８．５／２６．５／２３．５／１．５）、（４８．５／２６．５／２４．０／１．０）、（４８．５／２７．０／２２．５／２．０）、（４８．５／２７．０／２３．０／１．５）、（４８．５／２７．０／２３．５／１．０）、（４８．５／２７．５／２２．０／２．０）、（４８．５／２７．５／２２．５／１．５）、（４８．５／２７．５／２３．０／１．０）、（４８．５／２８．０／２１．５／２．０）、（４８．５／２８．０／２２．０／１．５）、（４８．５／２８．０／２２．５／１．０）、（４８．５／２８．５／２１．０／２．０）、（４８．５／２８．５／２１．５／１．５）、（４８．５／２８．５／２２．０／１．０）、（４８．５／２９．０／２０．５／２．０）、（４８．５／２９．０／２１．０／１．５）、（４８．５／２９．０／２１．５／１．０）、（４８．５／２９．５／２０．０／２．０）、（４８．５／２９．５／２０．５／１．５）、（４８．５／２９．５／２１．０／１．０）、（４８．５／３０．０／１９．５／２．０）、（４８．５／３０．０／２０．０／１．５）、（４８．５／３０．０／２０．５／１．０）、（４８．５／３０．５／１９．０／２．０）、（４８．５／３０．５／１９．５／１．５）、（４８．５／３０．５／２０．０／１．０）、（４８．５／３１．０／１８．５／２．０）、（４８．５／３１．０／１９．０／１．５）、（４８．５／３１．０／１９．５／１．０）、（４８．５／３１．５／１８．０／２．０）、（４８．５／３１．５／１８．５／１．５）、（４８．５／３１．５／１９．０／１．０）、（４８．５／３２．０／１７．５／２．０）、（４８．５／３２．０／１８．０／１．５）、（４８．５／３２．０／１８．５／１．０）、（４８．５／３２．５／１７．０／２．０）、（４８．５／３２．５／１７．５／１．５）、（４８．５／３２．５／１８．０／１．０）、（４８．５／３３．０／１６．５／２．０）、（４８．５／３３．０／１７．０／１．５）、（４８．５／３３．０／１７．５／１．０）、（４８．５／３３．５／１６．０／２．０）、（４８．５／３３．５／１６．５／１．５）、（４８．５／３３．５／１７．０／１．０）、（４８．５／３４．０／１５．５／２．０）、（４８．５／３４．０／１６．０／１．５）、（４８．５／３４．０／１６．５／１．０）、（４８．５／３４．５／１５．０／２．０）、（４８．５／３４．５／１５．５／１．５）、（４８．５／３４．５／１６．０／１．０）、（４８．５／３５．０／１５．０／１．５）、（４８．５／３５．０／１５．５／１．０）、（４８．５／３５．５／１５．０／１．０）、（４９．０／２５．０／２４．０／２．０）、（４９．０／２５．０／２４．５／１．５）、（４９．０／２５．０／２５．０／１．０）、（４９．０／２５．５／２３．５／２．０）、（４９．０／２５．５／２４．０／１．５）、（４９．０／２５．５／２４．５／１．０）、（４９．０／２６．０／２３．０／２．０）、（４９．０／２６．０／２３．５／１．５）、（４９．０／２６．０／２４．０／１．０）、（４９．０／２６．５／２２．５／２．０）、（４９．０／２６．５／２３．０／１．５）、（４９．０／２６．５／２３．５／１．０）、（４９．０／２７．０／２２．０／２．０）、（４９．０／２７．０／２２．５／１．５）、（４９．０／２７．０／２３．０／１．０）、（４９．０／２７．５／２１．５／２．０）、（４９．０／２７．５／２２．０／１．５）、（４９．０／２７．５／２２．５／１．０）、（４９．０／２８．０／２１．０／２．０）、（４９．０／２８．０／２１．５／１．５）、（４９．０／２８．０／２２．０／１．０）、（４９．０／２８．５／２０．５／２．０）、（４９．０／２８．５／２１．０／１．５）、（４９．０／２８．５／２１．５／１．０）、（４９．０／２９．０／２０．０／２．０）、（４９．０／２９．０／２０．５／１．５）、（４９．０／２９．０／２１．０／１．０）、（４９．０／２９．５／１９．５／２．０）、（４９．０／２９．５／２０．０／１．５）、（４９．０／２９．５／２０．５／１．０）、（４９．０／３０．０／１９．０／２．０）、（４９．０／３０．０／１９．５／１．５）、（４９．０／３０．０／２０．０／１．０）、（４９．０／３０．５／１８．５／２．０）、（４９．０／３０．５／１９．０／１．５）、（４９．０／３０．５／１９．５／１．０）、（４９．０／３１．０／１８．０／２．０）、（４９．０／３１．０／１８．５／１．５）、（４９．０／３１．０／１９．０／１．０）、（４９．０／３１．５／１７．５／２．０）、（４９．０／３１．５／１８．０／１．５）、（４９．０／３１．５／１８．５／１．０）、（４９．０／３２．０／１７．０／２．０）、（４９．０／３２．０／１７．５／１．５）、（４９．０／３２．０／１８．０／１．０）、（４９．０／３２．５／１６．５／２．０）、（４９．０／３２．５／１７．０／１．５）、（４９．０／３２．５／１７．５／１．０）、（４９．０／３３．０／１６．０／２．０）、（４９．０／３３．０／１６．５／１．５）、（４９．０／３３．０／１７．０／１．０）、（４９．０／３３．５／１５．５／２．０）、（４９．０／３３．５／１６．０／１．５）、（４９．０／３３．５／１６．５／１．０）、（４９．０／３４．０／１５．０／２．０）、（４９．０／３４．０／１５．５／１．５）、（４９．０／３４．０／１６．０／１．０）、（４９．０／３４．５／１５．０／１．５）、（４９．０／３４．５／１５．５／１．０）、（４９．０／３５．０／１５．０／１．０）、（４９．５／２５．０／２３．５／２．０）、（４９．５／２５．０／２４．０／１．５）、（４９．５／２５．０／２４．５／１．０）、（４９．５／２５．５／２３．０／２．０）、（４９．５／２５．５／２３．５／１．５）、（４９．５／２５．５／２４．０／１．０）、（４９．５／２６．０／２２．５／２．０）、（４９．５／２６．０／２３．０／１．５）、（４９．５／２６．０／２３．５／１．０）、（４９．５／２６．５／２２．０／２．０）、（４９．５／２６．５／２２．５／１．５）、（４９．５／２６．５／２３．０／１．０）、（４９．５／２７．０／２１．５／２．０）、（４９．５／２７．０／２２．０／１．５）、（４９．５／２７．０／２２．５／１．０）、（４９．５／２７．５／２１．０／２．０）、（４９．５／２７．５／２１．５／１．５）、（４９．５／２７．５／２２．０／１．０）、（４９．５／２８．０／２０．５／２．０）、（４９．５／２８．０／２１．０／１．５）、（４９．５／２８．０／２１．５／１．０）、（４９．５／２８．５／ ２０．０／２．０）、（４９．５／２８．５／２０．５／１．５）、（４９．５／２８．５／２１．０／１．０）、（４９．５／２９．０／１９．５／２．０）、（４９．５／２９．０／２０．０／１．５）、（４９．５／２９．０／２０．５／１．０）、（４９．５／２９．５／１９．０／２．０）、（４９．５／２９．５／１９．５／１．５）、（４９．５／２９．５／２０．０／１．０）、（４９．５／３０．０／１８．５／２．０）、（４９．５／３０．０／１９．０／１．５）、（４９．５／３０．０／１９．５／１．０）、（４９．５／３０．５／１８．０／２．０）、（４９．５／３０．５／１８．５／１．５）、（４９．５／３０．５／１９．０／１．０）、（４９．５／３１．０／１７．５／２．０）、（４９．５／３１．０／１８．０／１．５）、（４９．５／３１．０／１８．５／１．０）、（４９．５／３１．５／１７．０／２．０）、（４９．５／３１．５／１７．５／１．５）、（４９．５／３１．５／１８．０／１．０）、（４９．５／３２．０／１６．５／２．０）、（４９．５／３２．０／１７．０／１．５）、（４９．５／３２．０／１７．５／１．０）、（４９．５／３２．５／１６．０／２．０）、（４９．５／３２．５／１６．５／１．５）、（４９．５／３２．５／１７．０／１．０）、（４９．５／３３．０／１５．５／２．０）、（４９．５／３３．０／１６．０／１．５）、（４９．５／３３．０／１６．５／１．０）、（４９．５／３３．５／１５．０／２．０）、（４９．５／３３．５／１５．５／１．５）、（４９．５／３３．５／１６．０／１．０）、（４９．５／３４．０／１５．０／１．５）、（４９．５／３４．０／１５．５／１．０）、（４９．５／３４．５／１５．０／１．０）、（５０．０／２５．０／２３．０／２．０）、（５０．０／２５．０／２３．５／１．５）、（５０．０／２５．０／２４．０／１．０）、（５０．０／２５．５／２２．５／２．０）、（５０．０／２５．５／２３．０／１．５）、（５０．０／２５．５／２３．５／１．０）、（５０．０／２６．０／２２．０／２．０）、（５０．０／２６．０／２２．５／１．５）、（５０．０／２６．０／２３．０／１．０）、（５０．０／２６．５／２１．５／２．０）、（５０．０／２６．５／２２．０／１．５）、（５０．０／２６．５／２２．５／１．０）、（５０．０／２７．０／２１．０／２．０）、（５０．０／２７．０／２１．５／１．５）、（５０．０／２７．０／２２．０／１．０）、（５０．０／２７．５／２０．５／２．０）、（５０．０／２７．５／２１．０／１．５）、（５０．０／２７．５／２１．５／１．０）、（５０．０／２８．０／２０．０／２．０）、（５０．０／２８．０／２０．５／１．５）、（５０．０／２８．０／２１．０／１．０）、（５０．０／２８．５／１９．５／２．０）、（５０．０／２８．５／２０．０／１．５）、（５０．０／２８．５／２０．５／１．０）、（５０．０／２９．０／１９．０／２．０）、（５０．０／２９．０／１９．５／１．５）、（５０．０／２９．０／２０．０／１．０）、（５０．０／２９．５／１８．５／２．０）、（５０．０／２９．５／１９．０／１．５）、（５０．０／２９．５／１９．５／１．０）、（５０．０／３０．０／１８．０／２．０）、（５０．０／３０．０／１８．５／１．５）、（５０．０／３０．０／１９．０／１．０）、（５０．０／３０．５／１７．５／２．０）、（５０．０／３０．５／１８．０／１．５）、（５０．０／３０．５／１８．５／１．０）、（５０．０／３１．０／１７．０／２．０）、（５０．０／３１．０／１７．５／１．５）、（５０．０／３１．０／１８．０／１．０）、（５０．０／３１．５／１６．５／２．０）、（５０．０／３１．５／１７．０／１．５）、（５０．０／３１．５／１７．５／１．０）、（５０．０／３２．０／１６．０／２．０）、（５０．０／３２．０／１６．５／１．５）、（５０．０／３２．０／１７．０／１．０）、（５０．０／３２．５／１５．５／２．０）、（５０．０／３２．５／１６．０／１．５）、（５０．０／３２．５／１６．５／１．０）、（５０．０／３３．０／１５．０／２．０）、（５０．０／３３．０／１５．５／１．５）、（５０．０／３３．０／１６．０／１．０）、（５０．０／３３．５／１５．０／１．５）、（５０．０／３３．５／１５．５／１．０）、（５０．０／３４．０／１５．０／１．０）、（５０．５／２５．０／２２．５／２．０）、（５０．５／２５．０／２３．０／１．５）、（５０．５／２５．０／２３．５／１．０）、（５０．５／２５．５／２２．０／２．０）、（５０．５／２５．５／２２．５／１．５）、（５０．５／２５．５／２３．０／１．０）、（５０．５／２６．０／２１．５／２．０）、（５０．５／２６．０／２２．０／１．５）、（５０．５／２６．０／２２．５／１．０）、（５０．５／２６．５／２１．０／２．０）、（５０．５／２６．５／２１．５／１．５）、（５０．５／２６．５／２２．０／１．０）、（５０．５／２７．０／２０．５／２．０）、（５０．５／２７．０／２１．０／１．５）、（５０．５／２７．０／２１．５／１．０）、（５０．５／２７．５／２０．０／２．０）、（５０．５／２７．５／２０．５／１．５）、（５０．５／２７．５／２１．０／１．０）、（５０．５／２８．０／１９．５／２．０）、（５０．５／２８．０／２０．０／１．５）、（５０．５／２８．０／２０．５／１．０）、（５０．５／２８．５／１９．０／２．０）、（５０．５／２８．５／１９．５／１．５）、（５０．５／２８．５／２０．０／１．０）、（５０．５／２９．０／１８．５／２．０）、（５０．５／２９．０／１９．０／１．５）、（５０．５／２９．０／１９．５／１．０）、（５０．５／２９．５／１８．０／２．０）、（５０．５／２９．５／１８．５／１．５）、（５０．５／２９．５／１９．０／１．０）、（５０．５／３０．０／１７．５／２．０）、（５０．５／３０．０／１８．０／１．５）、（５０．５／３０．０／１８．５／１．０）、（５０．５／３０．５／１７．０／２．０）、（５０．５／３０．５／１７．５／１．５）、（５０．５／３０．５／１８．０／１．０）、（５０．５／３１．０／１６．５／２．０）、（５０．５／３１．０／１７．０／１．５）、（５０．５／３１．０／１７．５／１．０）、（５０．５／３１．５／１６．０／２．０）、（５０．５／３１．５／１６．５／１．５）、（５０．５／３１．５／１７．０／１．０）、（５０．５／３２．０／１５．５／２．０）、（５０．５／３２．０／１６．０／１．５）、（５０．５／３２．０／１６．５／１．０）、（５０．５／３２．５／１５．０／２．０）、（５０．５／３２．５／１５．５／１．５）、（５０．５／３２．５／１６．０／１．０）、（５０．５／３３．０／１５．０／１．５）、（５０．５／３３．０／１５．５／１．０）、（５０．５／３３．５／１５．０／１．０）、（５１．０／２５．０／２２．０／２．０）、（５１．０／２５．０／２２．５／１．５）、（５１．０／２５．０／２３．０／１．０）、（５１．０／２５．５／２１．５／２．０）、（５１．０／２５．５／２２．０／１．５）、（５１．０／２５．５／２２．５／１．０）、（５１．０／２６．０／２１．０／２．０）、（５１．０／２６．０／２１．５／１．５）、（５１．０／２６．０／２２．０／１．０）、（５１．０／２６．５／２０．５／２．０）、（５１．０／２６．５／２１．０／１．５）、（５１．０／２６．５／２１．５／１．０）、（５１．０／２７．０／２０．０／２．０）、（５１．０／２７．０／２０．５／１．５）、（５１．０／２７．０／２１．０／１．０）、（５１．０／２７．５／１９．５／２．０）、（５１．０／２７．５／２０．０／１．５）、（５１．０／２７．５／２０．５／１．０）、（５１．０／２８．０／１９．０／２．０）、（５１．０／２８．０／１９．５／１．５）、（５１．０／２８．０／２０．０／１．０）、（５１．０／２８．５／１８．５／２．０）、（５１．０／２８．５／１９．０／１．５）、（５１．０／２８．５／１９．５／１．０）、（５１．０／２９．０／１８．０／２．０）、（５１．０／２９．０／１８．５／１．５）、（５１．０／２９．０／１９．０／１．０）、（５１．０／２９．５／１７．５／２．０）、（５１．０／２９．５／１８．０／１．５）、（５１．０／２９．５／１８．５／１．０）、（５１．０／３０．０／１７．０／２．０）、（５１．０／３０．０／１７．５／１．５）、（５１．０／３０．０／１８．０／１．０）、（５１．０／３０．５／１６．５／２．０）、（５１．０／３０．５／１７．０／１．５）、（５１．０／３０．５／１７．５／１．０）、（５１．０／３１．０／１６．０／２．０）、（５１．０／３１．０／１６．５／１．５）、（５１．０／３１．０／１７．０／１．０）、（５１．０／３１．５／１５．５／２．０）、（５１．０／３１．５／１６．０／１．５）、（５１．０／３１．５／１６．５／１．０）、（５１．０／３２．０／１５．０／２．０）、（５１．０／３２．０／１５．５／１．５）、（５１．０／３２．０／１６．０／１．０）、（５１．０／３２．５／１５．０／１．５）、（５１．０／３２．５／１５．５／１．０）、（５１．０／３３．０／１５．０／１．０）、（５１．５／２５．０／２１．５／２．０）、（５１．５／２５．０／２２．０／１．５）、（５１．５／２５．０／２２．５／１．０）、（５１．５／２５．５／２１．０／２．０）、（５１．５／２５．５／２１．５／１．５）、（５１．５／２５．５／２２．０／１．０）、（５１．５／２６．０／２０．５／２．０）、（５１．５／２６．０／２１．０／１．５）、（５１．５／２６．０／２１．５／１．０）、（５１．５／２６．５／２０．０／２．０）、（５１．５／２６．５／２０．５／１．５）、（５１．５／２６．５／２１．０／１．０）、（５１．５／２７．０／１９．５／２．０）、（５１．５／２７．０／２０．０／１．５）、（５１．５／２７．０／２０．５／１．０）、（５１．５／２７．５／１９．０／２．０）、（５１．５／２７．５／１９．５／１．５）、（５１．５／２７．５／２０．０／１．０）、（５１．５／２８．０／１８．５／２．０）、（５１．５／２８．０／１９．０／１．５）、（５１．５／２８．０／１９．５／１．０）、（５１．５／２８．５／１８．０／２．０）、（５１．５／２８．５／１８．５／１．５）、（５１．５／２８．５／１９．０／１．０）、（５１．５／２９．０／１７．５／２．０）、（５１．５／２９．０／１８．０／１．５）、（５１．５／２９．０／１８．５／１．０）、（５１．５／２９．５／１７．０／２．０）、（５１．５／２９．５／１７．５／１．５）、（５１．５／２９．５／１８．０／１．０）、（５１．５／３０．０／１６．５／２．０）、（５１．５／３０．０／１７．０／１．５）、（５１．５／３０．０／１７．５／１．０）、（５１．５／３０．５／１６．０／２．０）、（５１．５／３０．５／１６．５／１．５）、（５１．５／３０．５／１７．０／１．０）、（５１．５／３１．０／１５．５／２．０）、（５１．５／３１．０／１６．０／１．５）、（５１．５／３１．０／１６．５／１．０）、（５１．５／３１．５／１５．０／２．０）、（５１．５／３１．５／１５．５／１．５）、（５１．５／３１．５／１６．０／１．０）、（５１．５／３２．０／１５．０／１．５）、（５１．５／３２．０／１５．５／１．０）、（５１．５／３２．５／１５．０／１．０）、（５２．０／２５．０／２１．０／２．０）、（５２．０／２５．０／２１．５／１．５）、（５２．０／２５．０／２２．０／１．０）、（５２．０／２５．５／２０．５／２．０）、（５２．０／２５．５／２１．０／１．５）、（５２．０／２５．５／２１．５／１．０）、（５２．０／２６．０／２０．０／２．０）、（５２．０／２６．０／２０．５／１．５）、（５２．０／２６．０／２１．０／１．０）、（５２．０／２６．５／１９．５／２．０）、（５２．０／２６ ．５／２０．０／１．５）、（５２．０／２６．５／２０．５／１．０）、（５２．０／２７．０／１９．０／２．０）、（５２．０／２７．０／１９．５／１．５）、（５２．０／２７．０／２０．０／１．０）、（５２．０／２７．５／１８．５／２．０）、（５２．０／２７．５／１９．０／１．５）、（５２．０／２７．５／１９．５／１．０）、（５２．０／２８．０／１８．０／２．０）、（５２．０／２８．０／１８．５／１．５）、（５２．０／２８．０／１９．０／１．０）、（５２．０／２８．５／１７．５／２．０）、（５２．０／２８．５／１８．０／１．５）、（５２．０／２８．５／１８．５／１．０）、（５２．０／２９．０／１７．０／２．０）、（５２．０／２９．０／１７．５／１．５）、（５２．０／２９．０／１８．０／１．０）、（５２．０／２９．５／１６．５／２．０）、（５２．０／２９．５／１７．０／１．５）、（５２．０／２９．５／１７．５／１．０）、（５２．０／３０．０／１６．０／２．０）、（５２．０／３０．０／１６．５／１．５）、（５２．０／３０．０／１７．０／１．０）、（５２．０／３０．５／１５．５／２．０）、（５２．０／３０．５／１６．０／１．５）、（５２．０／３０．５／１６．５／１．０）、（５２．０／３１．０／１５．０／２．０）、（５２．０／３１．０／１５．５／１．５）、（５２．０／３１．０／１６．０／１．０）、（５２．０／３１．５／１５．０／１．５）、（５２．０／３１．５／１５．５／１．０）、（５２．０／３２．０／１５．０／１．０）、（５２．５／２５．０／２０．５／２．０）、（５２．５／２５．０／２１．０／１．５）、（５２．５／２５．０／２１．５／１．０）、（５２．５／２５．５／２０．０／２．０）、（５２．５／２５．５／２０．５／１．５）、（５２．５／２５．５／２１．０／１．０）、（５２．５／２６．０／１９．５／２．０）、（５２．５／２６．０／２０．０／１．５）、（５２．５／２６．０／２０．５／１．０）、（５２．５／２６．５／１９．０／２．０）、（５２．５／２６．５／１９．５／１．５）、（５２．５／２６．５／２０．０／１．０）、（５２．５／２７．０／１８．５／２．０）、（５２．５／２７．０／１９．０／１．５）、（５２．５／２７．０／１９．５／１．０）、（５２．５／２７．５／１８．０／２．０）、（５２．５／２７．５／１８．５／１．５）、（５２．５／２７．５／１９．０／１．０）、（５２．５／２８．０／１７．５／２．０）、（５２．５／２８．０／１８．０／１．５）、（５２．５／２８．０／１８．５／１．０）、（５２．５／２８．５／１７．０／２．０）、（５２．５／２８．５／１７．５／１．５）、（５２．５／２８．５／１８．０／１．０）、（５２．５／２９．０／１６．５／２．０）、（５２．５／２９．０／１７．０／１．５）、（５２．５／２９．０／１７．５／１．０）、（５２．５／２９．５／１６．０／２．０）、（５２．５／２９．５／１６．５／１．５）、（５２．５／２９．５／１７．０／１．０）、（５２．５／３０．０／１５．５／２．０）、（５２．５／３０．０／１６．０／１．５）、（５２．５／３０．０／１６．５／１．０）、（５２．５／３０．５／１５．０／２．０）、（５２．５／３０．５／１５．５／１．５）、（５２．５／３０．５／１６．０／１．０）、（５２．５／３１．０／１５．０／１．５）、（５２．５／３１．０／１５．５／１．０）、（５２．５／３１．５／１５．０／１．０）、（５３．０／２５．０／２０．０／２．０）、（５３．０／２５．０／２０．５／１．５）、（５３．０／２５．０／２１．０／１．０）、（５３．０／２５．５／１９．５／２．０）、（５３．０／２５．５／２０．０／１．５）、（５３．０／２５．５／２０．５／１．０）、（５３．０／２６．０／１９．０／２．０）、（５３．０／２６．０／１９．５／１．５）、（５３．０／２６．０／２０．０／１．０）、（５３．０／２６．５／１８．５／２．０）、（５３．０／２６．５／１９．０／１．５）、（５３．０／２６．５／１９．５／１．０）、（５３．０／２７．０／１８．０／２．０）、（５３．０／２７．０／１８．５／１．５）、（５３．０／２７．０／１９．０／１．０）、（５３．０／２７．５／１７．５／２．０）、（５３．０／２７．５／１８．０／１．５）、（５３．０／２７．５／１８．５／１．０）、（５３．０／２８．０／１７．０／２．０）、（５３．０／２８．０／１７．５／１．５）、（５３．０／２８．０／１８．０／１．０）、（５３．０／２８．５／１６．５／２．０）、（５３．０／２８．５／１７．０／１．５）、（５３．０／２８．５／１７．５／１．０）、（５３．０／２９．０／１６．０／２．０）、（５３．０／２９．０／１６．５／１．５）、（５３．０／２９．０／１７．０／１．０）、（５３．０／２９．５／１５．５／２．０）、（５３．０／２９．５／１６．０／１．５）、（５３．０／２９．５／１６．５／１．０）、（５３．０／３０．０／１５．０／２．０）、（５３．０／３０．０／１５．５／１．５）、（５３．０／３０．０／１６．０／１．０）、（５３．０／３０．５／１５．０／１．５）、（５３．０／３０．５／１５．５／１．０）、（５３．０／３１．０／１５．０／１．０）、（５３．５／２５．０／１９．５／２．０）、（５３．５／２５．０／２０．０／１．５）、（５３．５／２５．０／２０．５／１．０）、（５３．５／２５．５／１９．０／２．０）、（５３．５／２５．５／１９．５／１．５）、（５３．５／２５．５／２０．０／１．０）、（５３．５／２６．０／１８．５／２．０）、（５３．５／２６．０／１９．０／１．５）、（５３．５／２６．０／１９．５／１．０）、（５３．５／２６．５／１８．０／２．０）、（５３．５／２６．５／１８．５／１．５）、（５３．５／２６．５／１９．０／１．０）、（５３．５／２７．０／１７．５／２．０）、（５３．５／２７．０／１８．０／１．５）、（５３．５／２７．０／１８．５／１．０）、（５３．５／２７．５／１７．０／２．０）、（５３．５／２７．５／１７．５／１．５）、（５３．５／２７．５／１８．０／１．０）、（５３．５／２８．０／１６．５／２．０）、（５３．５／２８．０／１７．０／１．５）、（５３．５／２８．０／１７．５／１．０）、（５３．５／２８．５／１６．０／２．０）、（５３．５／２８．５／１６．５／１．５）、（５３．５／２８．５／１７．０／１．０）、（５３．５／２９．０／１５．５／２．０）、（５３．５／２９．０／１６．０／１．５）、（５３．５／２９．０／１６．５／１．０）、（５３．５／２９．５／１５．０／２．０）、（５３．５／２９．５／１５．５／１．５）、（５３．５／２９．５／１６．０／１．０）、（５３．５／３０．０／１５．０／１．５）、（５３．５／３０．０／１５．５／１．０）、（５３．５／３０．５／１５．０／１．０）、（５４．０／２５．０／１９．０／２．０）、（５４．０／２５．０／１９．５／１．５）、（５４．０／２５．０／２０．０／１．０）、（５４．０／２５．５／１８．５／２．０）、（５４．０／２５．５／１９．０／１．５）、（５４．０／２５．５／１９．５／１．０）、（５４．０／２６．０／１８．０／２．０）、（５４．０／２６．０／１８．５／１．５）、（５４．０／２６．０／１９．０／１．０）、（５４．０／２６．５／１７．５／２．０）、（５４．０／２６．５／１８．０／１．５）、（５４．０／２６．５／１８．５／１．０）、（５４．０／２７．０／１７．０／２．０）、（５４．０／２７．０／１７．５／１．５）、（５４．０／２７．０／１８．０／１．０）、（５４．０／２７．５／１６．５／２．０）、（５４．０／２７．５／１７．０／１．５）、（５４．０／２７．５／１７．５／１．０）、（５４．０／２８．０／１６．０／２．０）、（５４．０／２８．０／１６．５／１．５）、（５４．０／２８．０／１７．０／１．０）、（５４．０／２８．５／１５．５／２．０）、（５４．０／２８．５／１６．０／１．５）、（５４．０／２８．５／１６．５／１．０）、（５４．０／２９．０／１５．０／２．０）、（５４．０／２９．０／１５．５／１．５）、（５４．０／２９．０／１６．０／１．０）、（５４．０／２９．５／１５．０／１．５）、（５４．０／２９．５／１５．５／１．０）、（５４．０／３０．０／１５．０／１．０）、（５４．５／２５．０／１８．５／２．０）、（５４．５／２５．０／１９．０／１．５）、（５４．５／２５．０／１９．５／１．０）、（５４．５／２５．５／１８．０／２．０）、（５４．５／２５．５／１８．５／１．５）、（５４．５／２５．５／１９．０／１．０）、（５４．５／２６．０／１７．５／２．０）、（５４．５／２６．０／１８．０／１．５）、（５４．５／２６．０／１８．５／１．０）、（５４．５／２６．５／１７．０／２．０）、（５４．５／２６．５／１７．５／１．５）、（５４．５／２６．５／１８．０／１．０）、（５４．５／２７．０／１６．５／２．０）、（５４．５／２７．０／１７．０／１．５）、（５４．５／２７．０／１７．５／１．０）、(54.5 / 27.5 / 16.0 / 2.0), (54.5 / 27.5 / 16.5 / 1.5), (54.5 / 27.5 / 17.0 / 1.0), (54.5 / 28.0 / 15.5 / 2.0), (54.5 / 28.0 / 16.0 / 1.5), (54.5 / 28.0 / 16.5 / 1.0), (54.5 / 28.5 / 15.0 / 2.0), (54.5 / 28.5 / 15.5 / 1.5), (54.5 / 28.5 / 16.0 / 1.0), (54.5 / 29.0 / 15.0 / 1.5), (54.5 / 29.0 / 15.5 / 1.0), (54.5 / 29.5 / 15.0 / 1.0), (55.0 / 25.0 / 18.0 / 2.0), (55.0 / 25.0 / 18.5 / 1.5), (55.0 / 25.0 / 19.0 / 1.0), (55.0 / 25.5 / 17.5 / 2.0), (55.0 / 25.5 / 18.0 / 1.5), (55.0 / 25.5 / 18.5 / 1.0), ( 55.0 / 26.0 / 17.0 / 2.0), (55.0 / 26.0 / 17.5 / 1.5), (55.0 / 26.0 / 18.0 / 1.0), (55.0 / 26.5 / 16.5 / 2.0), (55.0 / 26.5 / 17.0 / 1.5), (55.0 / 26.5 / 17.5 / 1.0), (55.0 / 27.0 / 16.0 / 2.0), (55.0 / 27.0 / 16.5 / 1.5), (55.0 / 27.0 / 17.0 / 1.0), (5 The values ​​are 5.0 / 27.5 / 15.5 / 2.0), (55.0 / 27.5 / 16.0 / 1.5), (55.0 / 27.5 / 16.5 / 1.0), (55.0 / 28.0 / 15.0 / 2.0), (55.0 / 28.0 / 15.5 / 1.5), (55.0 / 28.0 / 16.0 / 1.0), (55.0 / 28.5 / 15.0 / 1.5), (55.0 / 28.5 / 15.5 / 1.0), and (55.0 / 29.0 / 15.0 / 1.0).

[0076] 9. N / P Ratio In this disclosure, "N / P ratio" refers to the molar ratio of nitrogen atoms of cationic lipids in lipid nanoparticles to phosphate groups in nucleic acids. In the lipid nanoparticles of the present invention, the N / P ratio is 8.0 to 12.0, and excellent delivery to T cells is achieved within this range. The N / P ratio is, for example, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, preferably 8.0 to 10.0, 8.0 to 10.5, 8.0 to 11.0, 8.0 to 11.5, 8.5 to 10.0, 8.5 to 10.5, 8.5 to 11.0, 8.5 to 11.5, 8.5 to 12.0, 9.0 to 1 The ranges are 0.0, 9.0-10.5, 9.0-11.0, 9.0-11.5, 9.0-12.0, 9.5-10.0, 9.5-10.5, 9.5-11.0, 9.5-11.5, 9.5-12.0, 10.0-10.5, 10.0-11.0, 10.0-11.5, and 10.0-12.0, with a more preferred range of 9.0-11.0.

[0077] 10. Size of Lipid Nanoparticles The size of the lipid nanoparticles according to the present invention is preferably such that the average particle diameter is 400 nm or less, more preferably 300 nm or less, even more preferably 200 nm or less, and even more preferably 150 nm or less, in order to obtain high delivery efficiency to cells in living organisms. The average particle diameter of the lipid nanoparticles refers to the Z-mean particle diameter measured by dynamic light scattering (DLS). Measurement by dynamic light scattering can be performed by a conventional method using a commercially available DLS device, etc.

[0078] The morphology of the lipid nanoparticles according to the present invention is not particularly limited, but examples of morphologies when dispersed in an aqueous solvent include single-layer liposomes, multilayer liposomes, spherical micelles, or amorphous layered structures. The lipid nanoparticles according to the present invention are preferably single-layer liposomes or multilayer liposomes.

[0079] 11. Animals to be administered the lipid nanoparticles according to the present invention are not particularly limited and may be humans or other animals. Examples of non-human animals include mammals such as cattle, pigs, horses, sheep, goats, monkeys, dogs, cats, rabbits, mice, rats, hamsters, and guinea pigs, as well as birds such as chickens, quail, and ducks.

[0080] 12. Manufacturing Method In one embodiment, lipid nanoparticles of the Disclosure containing a target binding site are manufactured by a method comprising the steps of manufacturing untargeted lipid nanoparticles that do not contain a target binding site encapsulating nucleic acids, and linking the target binding site to the untargeted lipid nanoparticles. In another embodiment, lipid nanoparticles of the Disclosure containing a target binding site are manufactured by a method comprising the steps of manufacturing untargeted lipid nanoparticles that do not contain a target binding site encapsulating nucleic acids, and introducing a targeted polyalkylene glycol-modified lipid linked to a target binding site into the untargeted lipid nanoparticles. The above methods for manufacturing untargeted lipid nanoparticles are not particularly limited, and any method available to those skilled in the art can be employed. For example, lipid nanoparticles according to the present invention can be manufactured by an alcohol dilution method using a channel. This method involves introducing a solution in which a lipid component is dissolved in an alcohol solvent and a solution in which a water-soluble component to be encapsulated in the lipid nanoparticles is dissolved in an aqueous solvent from separate channels and combining them to produce lipid nanoparticles. Examples of aqueous solvents used in the alcohol dilution method include buffer solutions such as phosphate buffer, citrate buffer, and phosphate-buffered saline, as well as physiological saline and cell culture media. The above-mentioned non-targeted lipid nanoparticles may also be prepared by suspending lipid nanoparticles in an aqueous solution.

[0081] In another embodiment, lipid nanoparticles of the present disclosure containing a target binding site are produced by a method comprising the step of mixing nucleic acids, cationic lipids, and targeted polyalkylene glycol-modified lipids. The method for producing lipid nanoparticles according to the present invention is not particularly limited, and any method available to those skilled in the art can be employed. For example, lipid nanoparticles according to the present invention can be produced by the alcohol dilution method using the flow channel described above. Alternatively, for example, all lipid components can be dissolved in an organic solvent such as chloroform, and a lipid film can be formed by drying under reduced pressure using an evaporator or by spray drying using a spray dryer. Then, an aqueous solvent containing components to be encapsulated in the lipid nanoparticles, such as nucleic acids, can be added to the dried mixture, and the mixture can be further emulsified using an emulsifier such as a homogenizer, an ultrasonic emulsifier, or a high-pressure spray emulsifier. Liposomes can also be produced by methods well known for producing liposomes, such as reverse-phase evaporation. If it is desired to control the size of the lipid nanoparticles, extrusion (extrusion filtration) can be performed under high pressure using a membrane filter with uniform pore sizes.

[0082] The composition of the aqueous solvent (dispersion medium) is not particularly limited, but examples include buffers such as phosphate buffer, citrate buffer, and phosphate-buffered saline, physiological saline, and cell culture media. These aqueous solvents (dispersion mediums) can stably disperse lipid nanoparticles, but further additions such as sugars (aqueous solutions) such as monosaccharides like glucose, galactose, mannose, fructose, inositol, ribose, and xylose sugars, disaccharides such as lactose, sucrose, cellobiose, trehalose, and maltose, trisaccharides such as raffinose and melesinose, polysaccharides such as cyclodextrin, and sugar alcohols such as erythritol, xylitol, sorbitol, mannitol, and maltitol, or polyhydric alcohols (aqueous solutions) such as glycerin, diglycerin, polyglycerin, propylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, ethylene glycol monoalkyl ether, diethylene glycol monoalkyl ether, and 1,3-butylene glycol may also be added. To stably store lipid nanoparticles dispersed in this aqueous solvent for a long period, it is desirable to remove as much electrolyte as possible from the aqueous solvent in terms of physical stability, such as suppressing aggregation. Furthermore, in terms of the chemical stability of the lipids, it is desirable to set the pH of the aqueous solvent to slightly acidic to near neutral (pH 3.0 to 8.0) and / or remove dissolved oxygen by nitrogen bubbling or the like.

[0083] When freeze-drying or spray-drying an aqueous dispersion of lipid nanoparticles according to the present invention, stability may be improved by using sugars (aqueous solutions) such as monosaccharides including glucose, galactose, mannose, fructose, inositol, ribose, and xylose; disaccharides including lactose, sucrose, cellobiose, trehalose, and maltose; trisaccharides including raffinose and melesinose; polysaccharides including cyclodextrin; and sugar alcohols such as erythritol, xylitol, sorbitol, mannitol, and maltitol. Furthermore, when freezing the above aqueous dispersion, stability may be improved by using the aforementioned sugars or polyhydric alcohols (aqueous solutions) such as glycerin, diglycerin, polyglycerin, propylene glycol, polypropylene glycol, ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, ethylene glycol monoalkyl ether, diethylene glycol monoalkyl ether, and 1,3-butylene glycol. In one embodiment of the present invention, the lipid nanoparticles according to the present invention are freeze-dried.

[0084] In one aspect, the present invention relates to a pharmaceutical formulation containing lipid nanoparticles according to the present invention. The pharmaceutical formulation may contain a buffering agent. Examples of buffering agents include HEPES buffering agents, phosphate buffering agents, and Tris buffering agents. The pharmaceutical formulation may also contain a disaccharide. Examples of disaccharides include lactose, sucrose, cellobiose, trehalose, and maltose, with sucrose being preferred.

[0085] Synthesis of cationic lipids

[0086] In the embodiment, the following lipids (A) to (E) were used.

[0087] Lipid (B) is a lipid disclosed in International Publication No. 2022 / 071582 (Patent Document 1), and was produced according to the method described in said document.

[0088] Synthesis of Lipid (A) (1) (2-Phenyl-1,3-dioxane-5,5-diyl)dimethanol (1.12 g), 2-hexyldecanoic acid (2.69 g), and DMAP (61.1 mg) were dissolved in DCM (6.0 ml), and EDCI (2.11 g) was added and the mixture was stirred overnight at room temperature. Saturated ammonium chloride aqueous solution was added to the reaction solution and extracted three times with DCM. The organic layer was washed with saturated brine, and then dehydrated with sodium sulfate. After filtration, the solvent was removed under reduced pressure to obtain the crude product. (2) Methanol (32 ml), DCM (8.0 ml), and HCl (4 mol / L in 1,4-Dioxane, 4.0 ml) were added to the obtained crude product (2.10 g) and the mixture was stirred at room temperature for 4 hours. An excess amount of sodium bicarbonate was added to the reaction solution and it was concentrated under reduced pressure. Water and ethyl acetate were added to the residue and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, and then dehydrated with sodium sulfate. After filtration, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography [eluent: hexane / ethyl acetate] to obtain the target 2,2-bis(hydroxymethyl)propane-1,3-diyl bis(2-hexyldecanoate) (1.46 g). (3) In a container equipped with a calcium chloride tube, 4,4-diethoxy-N,N-diethylbutan-1-amine, p-toluenesulfonic acid monohydrate, and toluene were added and stirred overnight at 85°C. An excess amount of saturated sodium bicarbonate aqueous solution was added to the reaction solution and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, and then dehydrated with sodium sulfate. After filtration, the solvent was removed under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography to obtain the target lipid (A). 1H NMR (300 MHz, CDCl3) δ 4.48 (t, J = 5.1 Hz, 1H), 4.36 (s, 2H), 3.92 (d, J = 11.8 Hz, 2H), 3.83 (s, 2H), 3.60 (d, J = 11.8 Hz, 2H), 2.51 (q, J = 7.0 Hz, 4H), 2.44 (t, J = 6.9 Hz, 2H), 2.37-2.28 (m, 2H), 1.61-1.43 (m, 12H), 1.25 (brs, 40H), 1.04 (t, J = 7.1 Hz, 6H), 0.90-0.85 (m, 12H). Mass spectrometry (ESI) calculated value [M+H] + m / z = 738.7, measured value m / z = 738.7.

[0089] Synthesis of Lipid (C): 1.0 mmol of 7-(4-(dipropylamino)butyl)tridecane-1,7,13-triol was dissolved in 4 mL of dichloromethane, followed by the addition of 1.0 mmol of 2-decyldodecanoic acid, 0.10 mmol of DMAP (N,N-dimethyl-4-aminopyridine), and 3.0 mmol of EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide). The mixture was reacted overnight at room temperature. After removing the solvent using a rotary evaporator, the mixture was suspended in ethyl acetate and then separated and washed with 0.5 N aqueous sodium hydroxide solution and saturated saline solution. Anhydrous sodium sulfate was added to the organic layer to dehydrate it. After filtration, the solvent was removed using a rotary evaporator to obtain the crude product. The crude product was purified by ODS silica gel chromatography [eluent: water (0.1% TFA): acetonitrile (0.1% TFA) (continuous gradient)] to obtain 7-(4-(dipropylamino)butyl)-1,7-hydroxytridecane-13-(2-decyldodecanoate).

[0090] Next, 7-(4-(dipropylamino)butyl)-1,7-hydroxytridecane-13-(2-decyldodecanoate) (1.0 mmol) was dissolved in 4 mL of dichloromethane, and capric acid (1.2 mmol), DMAP (N,N-dimethyl-4-aminopyridine) (0.10 mmol), and EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) (3.0 mmol) were added. The mixture was reacted overnight at room temperature. After removing the solvent using a rotary evaporator, the mixture was suspended in ethyl acetate and then separated and washed with 0.5 N sodium hydroxide aqueous solution and saturated saline solution. Anhydrous sodium sulfate was added to the organic layer to dehydrate it. After filtration, the solvent was removed using a rotary evaporator to obtain the crude product. The crude product was purified by ODS silica gel chromatography [eluent: water (0.1% TFA): acetonitrile (0.1% TFA) (continuous gradient)] and silica gel chromatography [eluent: dichloromethane: methanol (continuous gradient)] to obtain the target lipid (C).

[0091] Synthesis of Lipids (D) (1) Synthesis of Compound a1 DL-10-camporsulfonic acid (CSA; 0.05 eq) was added to a mixture of 3,3-diethoxypropanenitrile (Combi-Blocks) (1.0 eq) and 1-heptanol (Combi-Blocks) (3 eq). The reaction mixture was heated at 100°C and stirred overnight. The reaction mixture was cooled to ambient temperature and purified on a silica gel short pad. The filtrate was concentrated under vacuum and dissolved in MeOH to a final concentration of 0.4 M. 8.0 M aqueous sodium hydroxide solution (1.5 eq) was added to the mixture. The mixture was stirred overnight at 60°C. The reaction mixture was diluted with ethyl acetate and saline solution. The aqueous layer was titrated to neutral pH with saturated ammonium chloride solution and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (ethyl acetate / hexane = 0-40%) to obtain compound a1. compound a1

[0092] (2) Synthesis of compound a2 The following compound a2 was synthesized according to the procedure described in WO2018 / 230710. compound a2

[0093] (3) Synthesis of lipid (D) Compound a2 (1.0 eq), compound a1 (2.3 eq), and 4-dimethylaminopyridine (DMAP) (Sigma-Aldrich, 0.2 eq) were dissolved in dichloromethane (DCM) (containing 0.2 M of compound a1) in a round-bottom flask, and 3-ethylcarbodiimide hydrochloride (EDCI) (TCI Chemicals, 2.8 eq) was added to the stirred solution. The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, saturated NaCl aqueous solution was added, and the mixture was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, evaporated, and the residue was purified by column chromatography to obtain lipid (D) (1.1 g). ESI+: m / z = 957.2.

[0094] Synthesis of lipid (E) (1) Synthesis of compound b1: b1 was obtained in the same manner as compound a1, except that 4,4-dimethoxybutanenitrile (AK Scientific) was used instead of 3,3-diethoxypropanenitrile. (2) Synthesis of lipid (E): Lipid (E) was obtained in the same manner as lipid (D), except that compound b1 was used instead of compound a1. ESI+: m / z = 985.2.

[0095] 1. General Manufacturing Procedure for Antibody-Conjugated Lipid Nanoparticles 1-1. Plasmid Preparation for Antibody Expression The kozak sequence, Ig K leader sequence, antibody-coding sequence, and linker sequence were cloned between sequence A at terminal 5 and sequence B at terminal 3 of the mammalian expression vector pcDNA3.4. The antibody-coding sequence underwent codon optimization for Cricetulus griseus (CHO) (GenScript Biotech Corporation, Piscataway, US).

[0096]

[0097] 1-2. Transient antibody expression: 30 mL of ExpiCHO Expression Medium (#A2910001, Thermo Fisher Scientific) and 1 mL of ExpiCHO-S cells thawed at 37°C (1 x 10⁶). 7 Cells / mL (Thermo Fisher Scientific) were added to a 125 mL flask (#4115-0500, Thermo Fisher Scientific) and cultured at 37°C, 8% CO2, and 125 rpm for 3–4 days (HERAcell CO2 incubator 150i, electromagnetic orbital shaker COSH6). The cell density was 1.0 x 10⁶. 6 Confirm that the concentration is 0.3–0.5 x 10 6 The cells were diluted to a concentration of cells / mL and cultured again at 37°C, 8% CO2, and 125 rpm for 3–4 days. This subculturing was repeated at least three times, and the cells were transferred to a 100 mL scale of medium in a 500 mL flask before plasmid transfection. Specifically, a solution of 80 μg of plasmid diluted in 4 mL of OptiPRO SFM (#12309019, Thermo Fisher Scientific) and a solution of 320 μL of ExpiFectamine CHO Reagent (#100033021, Thermo Fisher Scientific) diluted in 3.7 mL of OptiPRO SFM were mixed together, gently inverted, and the mixture was allowed to stand at room temperature for 1–5 minutes before being transfected to 6.0 x 10⁶ cells. 6The cells were added to a flask containing ExpiCHO-S cells diluted to cells / mL and cultured at 37°C, 8% CO2, and 125 rpm for 18–22 hours. Subsequently, a mixture of 600 μL of ExpiFectamine CHO Enhancer (#100033018, Thermo Fisher Scientific) and 24 mL of ExpiCHO Feed (#A29101-02, Thermo Fisher Scientific) was added to the ExpiCHO-S cells and cultured at 32°C, 5% CO2, and 125 rpm for 10–12 days. The cell culture medium was then transferred to a 50 mL tube, centrifuged at 4000 rpm, 4°C for 5 minutes, and the supernatant was filtered through a 0.22 μm or 0.45 μm syringe filter and stored frozen at -80°C.

[0098] 1-3. IMAC Purification of Antibodies A HisTrap column (HisTrap excel 5 mL, #17371206, Cytiva) was set on an AKTA go (Cytiva, Marlborough, MA, USA) and washed and equilibrated by delivering 25 mL of Wash Buffer (50 mM phosphate buffer pH 7.4, 300 mM NaCl) at a flow rate of 5.0 mL / min and a pressure resistance of 0.5 MPa. After injecting the supernatant of the ExpiCHO-S cell culture medium after antibody expression into the column, it was washed with 25 mL of Wash Buffer to remove unwanted components. A concentration gradient was applied to a mixture of Wash Buffer and Elution Buffer (50 mM phosphate buffer pH 7.4, 300 mM NaCl, 500 mM imidazole) so that the proportion of Elution Buffer changed linearly from 0% to 50% during the delivery of 50 mL, and the antibodies bound to the column were eluted. Each fraction was collected, the target fraction was identified by SDS-PAGE, and the fraction was transferred to an ultrafiltration filter unit (Vivaspin Turbo 15 3,000 MWCO, #VS15T91, Sartorius). The fraction was then concentrated by centrifugation at 4,000 × g at 4°C until the antibody concentration reached approximately 5–10 mg / mL.

[0099] 1-4. Affinity Purification of Antibodies with Protein A A 10 mL Pierce Centrifuge Columns (Thermo Fisher Scientific, #89898) were set in a Protein LoBind 50 mL tube (Eppendorf, #0030122240). 0.5 times the volume of the ExpiCHO-S cell culture supernatant to be purified was added to the Protein A resin suspension (Bipo Resin Protein A, #AAR-025, Protein Express Co., Ltd.), and the column was centrifuged at 3,000 × g at 4°C for 1 minute. The filtrate was discarded. The column was washed twice with an equal volume of DDW to the culture supernatant, and the filtrate was discarded. The column was then equilibrated twice with an equal volume of PBS to the culture supernatant, and the filtrate was discarded. The culture supernatant was added to the column and centrifuged at 3,000 × g at 4°C for 1 minute. The filtrate was added back to the same column and centrifuged again in the same manner, and the filtrate was discarded. Furthermore, the column was washed three times with an equal volume of PBS as the culture supernatant, and the filtrate was discarded. A new Protein LoBind 50 mL tube was filled with 0.025 times the volume of 1.0 M Tris-HCl pH9.0 (for neutralization) as the culture supernatant, and the column was transferred to this tube. 0.5 times the volume of Elution Buffer (0.1 M Glycine, pH2.5) as the culture supernatant was added to the column, and after standing for 1-2 minutes, the column was centrifuged at 3,000×g at 4°C for 1 minute to elute the antibodies bound to the resin. This elution procedure was repeated twice. The resulting filtrate was transferred to an ultrafiltration filter unit (Vivaspin Turbo 15 3,000 MWCO) and concentrated by centrifugation at 4,000×g at 4°C until the antibody concentration reached approximately 5-10 mg / mL.

[0100] 1-5. Antibody SEC Purification An SEC column (Superdex75 Increase 10 / 300 GL, #29148721, Cytiva) was set on an AKTA go (Cytiva, Marlborough, MA, USA) and washed and equilibrated by delivering 30 mL of PBS at a flow rate of 0.8 mL / min and a pressure resistance of 3.0 MPa. 500 μL of the sample purified with HisTrap column or Protein A resin was injected, and after delivering 24 mL of PBS, each fraction was collected and the target fraction was identified by SDS-PAGE. The obtained samples were transferred to an ultrafiltration filter unit (Vivaspin Turbo 15 3,000 MWCO) and concentrated by centrifugation at 4,000 × g at 4°C until the antibody concentration reached approximately 3–5 mg / mL. The concentration was determined by BCA assay and stored at -80°C.

[0101] 1-6. Preparation of GGGYPYDVPDYAK-(PEG)4-S-Acetyl Peptide The GGGYPYDVPDYAK peptide was synthesized using Fmoc solid-phase peptide synthesis. The N-terminal primary amino group was protected with a Boc group in an On resin peptide. Next, the protecting group (ivDde group) of the lysine side chain contained in the above sequence was selectively deprotected with 5% hydrazine / DMF. Subsequently, commercially available SAT(PEG)4 (PEGylated N-succinimidyl S-acetylthioacetate) was bonded to the deprotected primary amino group of the lysine side chain on the solid phase to synthesize GGGYPYDVPDYAK-(PEG)4-S-Acetyl. After washing the obtained On resin peptide with DCM, it was cleaved from the resin and deprotected using a TFA / water / TIS / DODT (92.5 / 2.5 / 2.5 / 2.5) cleavage cocktail. After deprotection, the obtained crude peptide was collected, precipitated with ether, and dried overnight. Subsequently, the peptide was purified by reverse-phase chromatography (C18 column, mobile phase (Solution A: H2O (containing 0.1% TFA), Solution B: Acetonitrile (containing 0.1% TFA))). After removing acetonitrile from the recovered purified solution using an evaporator, purified GGGYPYDVPDYAK-(PEG)4-S-Acetyl powder was obtained using a freeze-dryer (purity of 90% or higher).

[0102] 1-7. Pretreatment of antibodies for conjugates (in the case of antibody-Sortase linker adducts) The purified antibody-Sortase linker adduct was conjugated with the GGGYPYDVPDYAK-(PEG)4-S-Acetyl peptide via the Sortase reaction. Specifically, the mixture was diluted in DDW to a final concentration of 50 μM antibody, 20 μM Sortase A (Protein Express Co., Ltd., 17.9 kDa), 500 μM GGGYPYDVPDYAK-(PEG)4-S-Acetyl peptide, 1 mM CaCl2, 50 mM Tris-HCl (pH 7.9), and 150 mM NaCl. The mixture was prepared in 1 mL / tube and incubated at 37°C for 16 hours. Subsequently, the Sortase reaction solution was purified using the His tag. Specifically, a 10 mL Pierce Centrifuge Column (Thermo Fisher Scientific, #89965) equal to the amount of reaction solution to be purified was added to a 50 mL Protein LoBind tube with a Pierce Centrifuge Column (10 mL) (Thermo Fisher Scientific, #89898). The column was centrifuged at 700 × g, 4°C, for 1 minute, and the filtrate was discarded. 2.5 times the volume of PBS(-) was added to the column, and the column was centrifuged at 700 × g, 4°C, for 1 minute. This equilibration procedure was repeated a total of two times. The Sortase A reaction solution was added to the column, centrifuged at 700 × g, 4°C, for 1 minute, and the filtrate was added back to the same column. The column was centrifuged again at 700 × g, 4°C, for 1 minute, and the filtrate was collected. The column was then washed three times with 0.5 times the volume of PBS(-) and the filtrate was collected. The obtained filtrate was centrifuged at 4000 g and 4°C using an ultrafiltration filter unit (Vivaspin Turbo 15 3,000 MWCO) to concentrate it to approximately 3.2 mg / mL, and then SEC purification was performed. The Elution fraction was also obtained by adding 0.5 times the reaction solution volume of Elution Buffer (50 mM phosphate buffer pH 7.4, 300 mM NaCl, 500 mM imidazole), letting it stand for 2 minutes, and then centrifuging at 700 × g and 4°C for 1 minute.An SEC column (Superdex75 Increase 10 / 300 GL) was set on an AKTA go (Cytiva, Marlborough, MA, USA), washed and equilibrated, and then SEC purification of 500 μL of His-tagged samples was performed under conditions of 1x PBS, 0.8 mL / min, and a pressure of 3.0 MPa. Each fraction was collected, the target fraction was identified by SDS-PAGE, concentrated at 4000×g, 4°C on a Vivaspin Turbo 15 (3,000 MWCO), the concentration was determined by BCA assay, diluted to 2 mg / mL with PBS, and stored at -80°C. Deprotection of the S-Acetyl group was performed immediately before conjugation with LNP. An acetyl deprotection solution (Hydroxyamine 0.5 M (Pierce® Hydroxylamine-HCl, 26103, Thermo Scientific), EDTA 25 mM (Nacalai Tesque, 06894-14), pH 7.2-7.5, PBS(-)) was prepared immediately before use. The prepared acetyl deprotection solution was mixed with 2 mg / mL of acetyl-protected antibody to adjust the final concentration to 1 mg / mL antibody, 0.05 M hydroxyamine, and 2.5 mM EDTA. The mixture was stirred at 25°C and 200 rpm for 2 hours to obtain SH-free antibody. The conjugate antibody produced in this section was used in the production of antibody-conjugated lipid nanoparticles used in Examples 1-5 below.

[0103] 1-8. Pretreatment of antibodies for conjugate (in the case of antibody-reduced linker adducts) The artificially introduced cysteine ​​contained in antibody-reduced linker adducts forms disulfide bonds with glutathione and cysteine ​​in the culture medium, so it needs to be reduced before conjugation with LNPs. Specifically, a reduced solution was prepared by adding 0.5 M TCEP solution (Fujifilm Wako Pure Chemical Industries, Ltd., 207-20151) to EDTA 25 mM buffer to a final TCEP concentration of 10 mM. 15 μL of the reduced solution and 15 μL of 2 mg / mL antibody solution were mixed and shaken at 200 rpm for 5 minutes. The reaction mixture was added to a Zeba™ Spin Desalting Column (Thermo Scientific™, 89882) that had been purged twice with EDTA 25 mM buffer, centrifuged at 1500 × g, 20°C for 4 minutes, and the filtrate was collected. The protein concentration in the filtrate was measured using NanoDrop Lite (Thermo Scientific®). Based on the measurement results, the filtrate was diluted with 25 mM EDTA buffer to prepare an SH-free antibody solution with a protein concentration of 0.6 mg / mL.

[0104] 1-9. Lipid solutions were prepared by dissolving a lipid mixture (cationic lipid, Cholesterol, DSPC, DMG-PEG2000, DSPE-PEG(2000)-maleimide) in 100% EtOH (Cholesterol: Nacalai Tesque, 08722-81) (DSPC (1,2-Distearoyl-sn-glycero-3-phosphocholine): COATSOME MC-8080, NOF Corporation) (DMG-PEG2000 (1,2-Dimyristoyl-rac-glycero-3-methylpolyoxyethylene): SUNBRIGHT GM-020, NOF Corporation) (DSPE-PEG(2000)-maleimide (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[maleimide(polyethylene glycol)-2000] (ammonium salt)): Avanti Polar Lipids, 880126P). The lipid concentration was adjusted so that the final lipid concentration after mixing with the nucleic acid solution was 2–5 mM. The nucleic acid solution was prepared by diluting CleanCap mCherry mRNA (5 moU) (TriLink BioTechnologies, Inc., L-7203-5) with 50 mM citrate buffer solution (Citric Acid: FUJIFILM Wako Pure Chemical Corporation, 030-5525, Sodium citrate dihydrate: Sigma-Aldrich, W302600). The ratio of lipid to nucleic acid (N / P ratio) was set to 10.0, and the volume was adjusted to lipid:nucleic acid = 25:75 (Note that the N / P ratio of LNP in Examples 1–3 and 5 is 10.0 in all cases. The N / P ratio of LNP in Example 4 is as described in that example). The obtained lipid solution and nucleic acid solution were mixed at room temperature using a NanoAssemblr instrument (NanoAssemblr® Ignite®, Precision Nanosystems) at a rate of 3 ml / min for the lipid solution and 9 ml / min for the nucleic acid solution, and the solution containing the composition was collected.The obtained solution was diluted by the same volume with 9% sucrose and PBS buffer solution (PBS: Phosphate Buffered Saline (PBS) Tablets, pH 7.4, T9181; sucrose: Fujifilm Wako Pure Chemical Industries, 196-00015), and dialyzed against 9% sucrose and 20 mM HEPES buffer solution at 4°C for 16 to 24 hours using SpectraPor® 4 Dialysis Membrane (12-14kDa) (REPLIGEN, 132703). Subsequently, the solution was concentrated by ultrafiltration using Amicon Ultra-15 100kDa (Merck Millipore, UFC910024) and sterilized using a sterile syringe filter (φ13mm / 0.2μm) (Pall Corporation, 4602).

[0105] 1-10. Conjugation of untargeted LNPs with antibodies SH-free antibodies were added to an untargeted LNP solution containing maleimide in a ratio of 0.03 mol% or 0.1 mol% relative to the total lipid moles multiplied by the mRNA yield, and the antibody and LNPs were conjugated by stirring at 25°C and 200 rpm for 2 hours. Subsequently, five times the amount of L-Cysteine・HCl・HO (44889, Thermo Fisher Scientific) relative to the moles of DSPE-PEG(2000)-maleimide was added to quench the unreacted maleimide. Then, the antibody-conjugated LNPs were added to Spectra / Por® Float-A-Lyzer® G2 (MWCO: 1000kDa) (REPLIGEN, G235037), and dialysis was performed three times in a 9% sucrose, PBS buffer solution at 4°C for 2 to 12 hours. The obtained antibody-conjugated LNPs were sterilized using a sterile syringe filter (φ13mm / 0.2μm) (Pall Corporation, 4602) and stored at -80°C.

[0106] 1-11. Measurement of the physicochemical properties of antibody-conjugated LNPs. The average particle size and PDI of LNPs were measured using a Zetasizer Nano ZSP instrument (Malvern Instruments, Malvern, UK) after adding 5 μL of LNPs to 500 μL of D-PBS(-).

[0107] 1-12. Measurement of mRNA inclusion rate in antibody-conjugated LNPs The mRNA inclusion rate in antibody-conjugated LNPs was measured using Ribogreen reagent (Invitrogen, #R114491). Specifically, measurement solution A was prepared by diluting the LNP solution with TE buffer to approximately 8 μg mRNA / mL. Measurement solution B was also prepared by diluting the LNP solution with TE buffer to approximately 1.2 μg mRNA / mL and containing 1% (w / w) X-triton 100 (Sigma-Aldrich, T8787-50ML). 100 μL of each measurement solution and 100 μL of Ribogreen reagent diluted 200-fold with TE buffer were mixed on a 96-well microplate, incubated at room temperature for 5 minutes, and the fluorescence intensity at an excitation wavelength of 485 nm and a measurement wavelength of 528 nm was measured. Nucleic acid concentration was calculated using a calibration curve created for nucleic acid concentrations ranging from 0 to 2.5 μg / mL. The mRNA inclusion rate in antibody-conjugated LNPs was calculated using the following formula: Inclusion rate % = ((Nucleic acid concentration of measurement solution B (μg / mL) - Nucleic acid concentration of measurement solution A (μg / mL)) ÷ Nucleic acid concentration of measurement solution B (μg / mL) × 100)

[0108] 1-13. Antibody Quantification in LNPs Protein quantification was performed according to the protocol of the Pierce BCA Protein Assay Kit. Specifically, the 2 mg / mL Albumin standard included in the kit was diluted with PBS to create a calibration curve ranging from 0 to 1000 μg / mL in 25 μL / wells. In addition, 25 μL / well of 100 μg mRNA / mL LNPs were added. The kit's included solutions A and B were mixed in a 50:1 ratio and 200 μL was added to each well. After sealing and incubation at 37°C for 30 minutes at 200 rpm, the absorbance at 562 nm was measured with a plate reader to quantify the protein concentration.

[0109] 1-14. Analysis of Antibody-Lipid Conjugates Sample Buffer was prepared by adding 200 μL of 1M DTT solution (Sigma, 43816) to 1000 μL of 2x Laemmli Sample Buffer (Bio-Rad, #161-0737). An equal volume of Sample Buffer was added to LNPs with 100 μg mRNA / mL, and the mixture was heated at 95°C for 5 minutes. The molecular weight marker was an equal mixture of Precision Plus Protein All Blue Standards and Precision Plus Protein Unstained Standards. Any kD Mini-Protean TGX Stain-Free Gels (Bio-Rad, Hercules, CA, USA) were set up in an electrophoresis apparatus (Bio-Rad, Mini-Protean Tetra cell), 1x Tris / Glycine / SDS buffer was poured in, and 10 μL of sample was loaded. Electrophoresis was then performed at 200 V for 30 minutes. Images were taken after UV irradiation with ChemiDoc XRS+ (Bio-rad). The gel was transferred to a PVDF membrane (Trans-Blot Turbo Mini PVDF Transfer Packs, Bio-Rad) using the Trans-Blot Turbo Blotting system (Bio-Rad). The membrane was placed in a container and immersed in 15 mL of Bullet Blocking One for Western Blotting (Nacalai tesque, 13779-14), and shaken at room temperature for 5 minutes. The membrane was immersed in 10 mL of PBS-T, pH 7.4 (x1), and shaken at room temperature for 3 minutes, repeating this three times. 2.5 μL of anti-hemagglutinin monoclonal antibody conjugated to peroxidase and 1 μL of Precision Protein StrepTactin-HRP Conjugate were added to 10 mL of PBS-T (x1) and mixed, the membrane was immersed, and shaken at room temperature for 30 minutes under light protection. The membrane was immersed in 10 mL of PBS-T (x1) and shaken for 3 minutes at room temperature, and this process was repeated three times.A membrane was immersed in 6 mL of a solution prepared by mixing equal volumes of two Clarity Western ECL Substrate (Bio-Rad) solutions immediately before use, and shaken at room temperature for 5 minutes. The membrane was imaged using ChemiDoc XRS Plus (Bio-Rad) to confirm the formation of antibody-lipid conjugates.

[0110] 2. General procedure for evaluating protein expression: Human peripheral blood mononuclear cells (Lonza) were introduced into NSG mice (NOD.Cg-PrkdcscidIl2rgtm1Wjl / SzJ), which are severely immunodeficient mice. 7 Cells / heads were transferred intravenously. Approximately two weeks after transplantation of PBMCs, each preparation was administered intravenously. 24 hours after preparation administration, the spleen was removed. After lysation and hemolysis of the spleen, a cell suspension was prepared. Dead cells were stained with Fixable Viability Stain 575V (BD Horizon™), and after Fc blocking, the cells were labeled with each antibody (see antibody list). Intracellular mCherry expression was measured using FACSymphony™ A1 (BD Biosciences). <Antibody List> Fluorescently Labeled Antibodies BB515 anti-hCD4 Antibody PE-Cy5 anti-mCD45 Antibody PE-Cy7 anti-hCD3 Antibody APC anti-hCD8 Antibody BV711 anti-hCD45 Antibody

[0111] 3. General procedure for analyzing mCherry expression in the liver using IVIS: Human peripheral blood mononuclear cells (Lonza) were introduced into NSG mice (NOD.Cg-PrkdcscidIl2rgtm1Wjl / SzJ), a severely immunodeficient mouse species, by 2 x 10⁻¹⁶ human peripheral blood mononuclear cells (Lonza). 7 Cells were transferred intravenously via cell / head transfer. Approximately two weeks after transplantation of PBMCs, each drug was administered intravenously. 24 hours after drug administration, the liver was removed and imaged in fluorescence mode using IVIS® Spectrum CT. The average fluorescence intensity was measured for each individual's liver using IVIS software.

[0112] Example 1 Each antibody-conjugate LNP containing mCheery mRNA, as listed in Table 2 below, was intravenously administered at 0.4 mg / kg to hPBMC-transplanted NSG mice. After 24 hours, the spleen was collected and mCherry MFI in CD8-positive T cells was evaluated by flow cytometry (Figure 1). In addition, mCherry expression in the liver was measured by IVIS after 24 hours, and the mCherry expression intensity was evaluated (Figure 2).

[0113] All antibody-2 conjugate lipid nanoparticles were shown to be carriers capable of selectively delivering mRNA to CD8-positive T cells. Furthermore, the results of calculating T cell mCherry expression / liver mCherry expression LNPs (Figure 3) showed that 4g was less likely to be delivered to the liver compared to other antibody-2 conjugate lipid nanoparticles, indicating that it is a carrier capable of selectively delivering mRNA to T cells.

[0114] Example 2 Antibody-conjugated LNPs 1a to 8a, as described in Tables 3 and 4 below, were prepared.

[0115]

[0116] NSG mouse (NOD.Cg-Prkdc), a severely immunodeficient mouse. scid Il2rg tm1Wjl Human peripheral blood mononuclear cells (Lonza) in / SzJ) are 2 x 10 7Cells / heads were transferred intravenously. Approximately two weeks after transplantation of PBMCs, each antibody-conjugated LNP containing mCherry mRNA was administered at a dose of 0.4 mg / kg. 24 hours after LNP administration, the spleen was removed, and mCherry MFI was measured in spleen CD3,CD8(+) T cells by flow cytometry. Simultaneously, the liver was removed, and the average mCherry fluorescence intensity was measured in each individual's liver using IVIS. The T cell expression level in the liver was calculated from the mCherry MFI in spleen CD3,CD8(+) T cells and the average mCherry fluorescence intensity in the liver. The results are shown in Figure 4. In Figure 4, for ease of comparison, the values ​​for LNP 2a, 4a, 6a, and 8a were calculated with the values ​​for LNP 1a, 3a, 5a, and 7a set to 1. Regardless of the type of cationic lipid, LNPs 2a, 4a, 6a, and 8a related to the present invention were all shown to be carriers that selectively deliver mRNA to liver cells compared to LNPs 1a, 3a, 5a, and 7a using known lipid compositions.

[0117] Each antibody-conjugate LNP containing mCherry mRNA was transfected into activated T cells at 0.02 μg / mL or 0.2 μg / mL, and the mCherry expression rate in CD8-positive or CD4-positive T cells was evaluated by flow cytometry after 24 hours. The results showed that all antibody-conjugate LNPs were carriers capable of selectively delivering mRNA to CD8-positive T cells.

[0118] Example 3 Antibody-conjugated LNPs 1b-9b, 11b-19b, and 21b-29b were prepared as described in Tables 5 and 6 below. For each of the LNPs 1b, 2b, 5b, 11b, 12b, 15b, 21b, 22b, and 25b, an increase in particle size and a low encapsulation rate were observed.

[0119]

[0120] NSG mouse (NOD.Cg-Prkdc), a severely immunodeficient mouse.scid Il2rg tm1Wjl Human peripheral blood mononuclear cells (Lonza) in / SzJ) are 2 x 10 7 Cells / heads were transferred intravenously. Approximately two weeks after transplantation of PBMCs, each antibody-conjugated LNP containing mCherry mRNA was administered at a dose of 0.4 mg / kg. 24 hours after LNP administration, the spleen was removed, and mCherry MFI in spleen CD3,CD8(+) T cells was measured by flow cytometry. Simultaneously, the liver was removed, and the average mCherry fluorescence intensity in each individual's liver was measured using IVIS. T cell expression levels in the liver were calculated from the mCherry MFI in spleen CD3,CD8(+) T cells and the average mCherry fluorescence intensity in the liver. The results are shown in Figures 5-7. LNPs 3b, 4b, and 7b were shown to be carriers that selectively deliver mRNA to the liver in a way that promotes T cell expression, compared to LNPs 5b, 8b, and 9b. A similar trend was observed even when the cationic lipid was changed. Specifically, LNPs 13b, 14b, and 17b were shown to be carriers that selectively deliver mRNA to the liver in a way that promotes T cell expression, compared to LNPs 15b, 18b, and 19b. Similarly, LNPs 23b, 24b, and 27b were shown to be carriers that selectively deliver mRNA to the liver in a way that promotes T cell expression, compared to LNPs 25b, 28b, and 29b.

[0121] Example 4: Antibody-conjugated LNPs 1c to 6c were prepared as described in Tables 7 and 8 below.

[0122]

[0123] NSG mouse (NOD.Cg-Prkdc), a severely immunodeficient mouse. scid Il2rg tm1Wjl Human peripheral blood mononuclear cells (Lonza) in / SzJ) are 2 x 10 7Cells / heads were transferred intravenously. Approximately two weeks after transplantation of PBMCs, each antibody-conjugated LNP containing mCherry mRNA was administered at a dose of 0.4 mg / kg. 24 hours after LNP administration, the spleen was removed, and mCherry MFI in spleen CD3,CD8(+) T cells was measured by flow cytometry. Simultaneously, the liver was removed, and the average mCherry fluorescence intensity in each individual's liver was measured using IVIS. T cell expression levels in the liver were calculated from the mCherry MFI in spleen CD3,CD8(+) T cells and the average mCherry fluorescence intensity in the liver. The results are shown in Figures 8 and 9. LNPs 1c, 3c, and 5c, adjusted for an N / P ratio of 10.0, were shown to be carriers capable of more selective delivery of mRNA to CD8-positive T cells compared to LNPs 2c, 4c, and 6c, which had an N / P ratio of 6.0.

[0124] Example 5 Antibody-conjugated LNPs 1d to 6d were prepared as described in Tables 9 and 10 below.

[0125]

[0126] Antibody-conjugated LNPs containing mCherry mRNA were transfected into activated T cells at 0.002 μg / mL, 0.02 μg / mL, or 0.2 μg / mL. After 24 hours, mCherry expression rates and mCherry MFI in CD8-positive or CD4-positive T cells were evaluated by flow cytometry. The results are shown in Figures 10 and 11. In the figures, NC represents a negative control LNP in which antibody 13 (a known anti-PSMA antibody, J591) was conjugated to LNP4d instead of antibody 1.

[0127] Conjugated LNPs 4d, 5d, and 6d with a total PEG content of 1.5 mol% were shown to be carriers that deliver mRNA more selectively to T cells than conjugated LNP 1d with a total PEG content of 2.5 mol%. Furthermore, conjugated LNPs 4d and 5d, in which the proportion of DSPE-PEG2K-maleimide within the 1.5 mol% total PEG content was 0.75 mol% or less, were shown to be carriers that deliver mRNA even more selectively to T cells.

Claims

1. Lipid nanoparticles comprising nucleic acids encapsulated within the lipid nanoparticles, cationic lipids, sterols or sterol derivatives, DSPCs, targeted polyalkylene glycol-modified lipids linked to a target binding site, and untargeted polyalkylene glycol-modified lipids not linked to a target binding site, wherein the target binding site targets a target site on a T cell, the amount of cationic lipids is 35.0 to 55.0 mol% of the total lipid amount of the lipid nanoparticles, the amount of sterols is 25.0 to 40.0 mol% of the total lipid amount of the lipid nanoparticles, the amount of DSPCs is 15.0 to 35.0 mol% of the total lipid amount of the lipid nanoparticles, and the N / P ratio is 8.0 to 12.

0.

2. Lipid nanoparticles according to claim 1, wherein the N / P ratio is 9.0 to 11.

0.

3. The lipid nanoparticle according to claim 1, wherein the total amount of the targeted polyalkylene glycol-modified lipid and the untargeted polyalkylene glycol-modified lipid is 1.0 to 2.2 mol% of the total lipid amount of the lipid nanoparticle.

4. The lipid nanoparticle according to claim 1, wherein the total amount of polyalkylene glycol-modified lipids linked to a target binding site and polyalkylene glycol-modified lipids not linked to a target binding site is 1.0 to 1.8 mol% of the total lipid amount of the lipid nanoparticle.

5. The lipid nanoparticle according to claim 1, wherein the target site on the T cell is CD2, CD3, CD4, CD5, CD6, CD7, or CD8.

6. The lipid nanoparticle according to claim 1, wherein the target site on the T cell is CD8.

7. The lipid nanoparticle according to claim 1, wherein the target binding site is an antibody or an antigen-binding fragment thereof.

8. The lipid nanoparticle according to claim 1, wherein the target binding site is an antibody, a Fab fragment, a Fab' fragment, an F(ab')2 fragment, an scFv, or a VHH antibody.

9. The lipid nanoparticle according to claim 1, wherein the target binding site is a VHH antibody.

10. The lipid nanoparticle according to claim 1, wherein the sterol or sterol derivative is cholesterol.

11. The lipid nanoparticle according to claim 1, wherein the ratio of the targeted polyalkylene glycol-modified lipid to the total of the targeted polyalkylene glycol-modified lipid and the untargeted polyalkylene glycol-modified lipid is greater than 0% and 60% or less.

12. The lipid nanoparticle according to claim 1, wherein the ratio of the targeted polyalkylene glycol-modified lipid to the total of the targeted polyalkylene glycol-modified lipid and the untargeted polyalkylene glycol-modified lipid is greater than 0% and 15% or less.

13. The lipid nanoparticle according to claim 1, wherein the amount of cationic lipid is 40.0 mol% of the total lipid amount of the lipid nanoparticle, the amount of sterol or sterol derivative is 38.5 mol% of the total lipid amount of the lipid nanoparticle, the amount of DSPC is 20.0 mol% of the total lipid amount of the lipid nanoparticle, and the sum of polyalkylene glycol-modified lipids linked to a target binding site and polyalkylene glycol-modified lipids not linked to a target binding site is 1.5 mol% of the total lipid amount of the lipid nanoparticle.

14. The lipid nanoparticle according to claim 1, wherein the amount of cationic lipid is 40.0 mol% of the total lipid amount of the lipid nanoparticle, the amount of sterol or sterol derivative is 28.5 mol% of the total lipid amount of the lipid nanoparticle, the amount of DSPC is 30.0 mol% of the total lipid amount of the lipid nanoparticle, and the sum of polyalkylene glycol-modified lipids linked to a target binding site and polyalkylene glycol-modified lipids not linked to a target binding site is 1.5 mol% of the total lipid amount of the lipid nanoparticle.

15. The lipid nanoparticle according to claim 1, wherein the amount of cationic lipid is 50.0 mol% of the total lipid amount of the lipid nanoparticle, the amount of sterol or sterol derivative is 28.5 mol% of the total lipid amount of the lipid nanoparticle, the amount of DSPC is 20.0 mol% of the total lipid amount of the lipid nanoparticle, and the sum of polyalkylene glycol-modified lipids linked to a target binding site and polyalkylene glycol-modified lipids not linked to a target binding site is 1.5 mol% of the total lipid amount of the lipid nanoparticle.

16. The lipid nanoparticle according to claim 1, wherein the targeted polyalkylene glycol-modified lipid comprises DSPE-PEG, and the untargeted polyalkylene glycol-modified lipid comprises DMG-PEG.

17. The lipid nanoparticle according to claim 1, wherein the target binding site is linked to the polyalkylene glycol of the targeted polyalkylene glycol-modified lipid via a linker.

18. The lipid nanoparticle according to claim 17, wherein the linker comprises a peptide of 1 to 50 units.

19. The linker is (Ser-Ser-Ser-Gly) m (Sequence ID 1) [wherein m is an integer from 1 to 5], (Glu-Ala-Ala-Ala-Lys) n (Sequence No. 2) [wherein n is an integer from 1 to 4], (Ala-Pro) ｐ [In the formula, p is an integer from 1 to 8], (His) ｑ Lipid nanoparticles according to claim 17, comprising at least one of the following: [wherein q is an integer from 1 to 10].

20. The linker is (OCH ２ CH ２ ) ｒ Lipid nanoparticles according to claim 17, comprising [wherein r is an integer from 1 to 10].

21. The linker is given by the following formula: Lipid nanoparticles according to claim 17, comprising a site indicated by [wherein the formula, the left arrow indicates linkage with the peptide, the right arrow indicates linkage with polyalkylene glycol, X is N or O, and r is an integer from 1 to 15].

22. The linker is represented as -Z1-Z2-, where Z1 is linked to the target binding site, Z2 is linked to the polyalkylene glycol, and Z1 is It is represented as, and Z2 is, Lipid nanoparticles according to claim 17, represented by the formula [wherein the left arrow indicates linkage to an adjacent Lys side chain amino group, the right arrow indicates linkage to a polyalkylene glycol, X is N or O, and r is an integer from 1 to 15].

23. The linker is represented as -Z1-Z2-, where Z1 is linked to the target binding site, Z2 is linked to the polyalkylene glycol, and Z1 is as follows: Z2 is one of the polypeptides shown, and Z2 is Lipid nanoparticles according to claim 17, represented by the formula [wherein the left arrow indicates linkage to the adjacent Cys side chain SH group, the right arrow indicates linkage to polyalkylene glycol, and X is N or O].

24. The lipid nanoparticle according to claim 1, wherein the untargeted polyalkylene glycol-modified lipid comprises a polyalkylene glycol-modified lipid in which polyalkylene glycol is modified with a reactive group, and a polyalkylene glycol-modified lipid in which polyalkylene glycol is unmodified.

25. The lipid nanoparticle according to claim 24, wherein the reactive group comprises a group selected from the group consisting of acetylene, transcyclooctene, cyclooctin, diarylcyclooctin, oxime, ketone, aldehyde, thiol, free cysteine, amine, maleimide, NHS (N-hydroxysuccinimide), NHS ester (N-hydroxysuccinimide ester), isocyanate, isothiocyanate, methyl ester phosphine, norbornene, tetrazine, methylcyclopropene, azetine, cyanide, azide, and dibenzocyclooctin.

26. The lipid nanoparticle according to claim 24, wherein the reactive group comprises maleimide.

27. The lipid nanoparticles according to claim 24, wherein the polyalkylene glycol-modified lipid, in which polyalkylene glycol is modified with a reactive group, comprises DSPE-PEG, and the polyalkylene glycol-modified lipid, in which polyalkylene glycol is not modified, comprises DMG-PEG.

28. The lipid nanoparticle according to claim 1, wherein the untargeted polyalkylene glycol-modified lipid comprises a polyalkylene glycol-modified lipid in which polyalkylene glycol is modified at the untargeting site, and a polyalkylene glycol-modified lipid in which polyalkylene glycol is unmodified.

29. The lipid nanoparticle according to claim 28, wherein the polyalkylene glycol-modified lipid, in which polyalkylene glycol is modified at a non-targeting site, contains DSPE-PEG, and the polyalkylene glycol-modified lipid, in which polyalkylene glycol is not modified, contains DMG-PEG.

30. The lipid nanoparticle according to claim 1, wherein the nucleic acid is siRNA, antisense nucleic acid, heteroduplex nucleic acid, miRNA, gRNA, or mRNA.

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