6b644029b0d48b0344bb542c8a229580 paper_publicado.pdf 814f9f8e882aa9b68687f7173a3287bd803f0e08 paper_publicado.pdf ff38599da11e10fd0669e2f910586eca5050aa40d4d596324d319e41e5124b28 paper_publicado.pdf Title: A myotropic AAV vector combined with skeletal muscle cis-regulatory elements improve glycogen clearance in mouse models of Pompe disease Subject: Molecular Therapy: Methods & Clinical Development, 33 (2025) 101464. doi:10.1016/j.omtm.2025.101464 Author: P. Sellier Creator: PTC Arbortext Layout Developer 12.2.6665/W-x64 Producer: PDFlib+PDI 10.0.2p2 (C++/Win64) CreationDate: Mon Apr 28 07:25:04 2025 CEST ModDate: Mon Apr 28 07:38:11 2025 CEST Custom Metadata: yes Metadata Stream: yes Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 24 Encrypted: no Page size: 602.986 x 782.986 pts Page rot: 0 File size: 16363078 bytes Optimized: yes PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- HelveticaNeue-Light Type 1 Builtin yes no yes 1842 0 HelveticaNeue-LightItalic Type 1 Builtin yes no yes 1846 0 LEJJPM+MinionPro-Regular Type 1C Custom yes yes yes 1850 0 NXKVRV+MinionPro-Bold Type 1C Custom yes yes yes 1856 0 YFGFQF+STIX-Bold Type 1C Custom yes yes yes 1853 0 DQGZZB+MinionPro-BoldIt Type 1C Custom yes yes yes 1867 0 CM_Maths_Symbols Type 1 Builtin yes no yes 1864 0 DTQHWI+MinionPro-It Type 1C Custom yes yes yes 1874 0 SNXVYO+STIX-Regular Type 1C Custom yes yes yes 1870 0 YLUYDT+Rockwell Type 1C Custom yes yes yes 1881 0 HelveticaNeue-Bold Type 1 Builtin yes no yes 222 0 HelveticaNeue-BoldItalic Type 1 Builtin yes no yes 232 0 HelveticaNeue-Roman Type 1 Builtin yes no yes 248 0 GHZMNM+Helvetica-Bold Type 1C WinAnsi yes yes no 14 0 HelveticaNeue-Italic Type 1 Builtin yes no yes 361 0 GHZMNM+Helvetica-Bold Type 1C WinAnsi yes yes no 54 0 ZWRFVC+STIX-Italic Type 1C Custom yes yes yes 499 0 TNHSPJ+Arial-BoldMT Type 1C Custom yes yes yes 763 0 XAJJON+Arial-BoldItalicMT Type 1C Custom yes yes yes 764 0 PETNKE+TimesNewRomanPS-BoldMT CID TrueType Identity-H yes yes yes 765 0 BCDEEE+Calibri TrueType WinAnsi yes yes no 784 0 BCDFEE+Calibri-Bold TrueType WinAnsi yes yes no 787 0 BCDGEE+Calibri-Italic TrueType WinAnsi yes yes no 780 0 BCDHEE+Calibri CID TrueType Identity-H yes yes yes 794 0 BCDIEE+Aptos TrueType WinAnsi yes yes no 800 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-10-30 03:12:41 CET RepresentationInformation: paper_publicado.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-10-29 04:41:33 CET Size: 16363078 Format: PDF Version: 1.7 Status: Well-Formed, but not valid SignatureMatches: PDF-hul ErrorMessage: Invalid indirect destination - referenced object 'fn1' cannot be found ID: PDF-HUL-149 ErrorMessage: edu.harvard.hul.ois.jhove.module.pdf.PdfInvalidException: Invalid indirect destination - referenced object 'fn1' cannot be found ID: PDF-HUL-122 Offset: 16306820 MIMEtype: application/pdf Profile: Linearized PDF PDFMetadata: Objects: 1985 FreeObjects: 1 IncrementalUpdates: 1 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: false CenterWindow: false DisplayDocTitle: true NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseOutlines Language: English Outlines: Item: Title: A myotropic AAV vector combined with skeletal muscle cis-regulatory elements improve glycogen clearance in mouse models of ... Destination: mk:title Children: Item: Title: Introduction Destination: mk:H1_1 Item: Title: Results Destination: mk:H1_2 Children: Item: Title: Engineered AAV capsids combined with optimized transgene expression cassettes result in superior glycogen clearance in skel ... Destination: mk:H2_1 Item: Title: Muscle-specific targeting with engineered AAV vectors achieves efficacy at lower vector doses compared to AAV9 in immunodef ... Destination: mk:H2_2 Item: Title: Discussion Destination: mk:H1_3 Item: Title: Materials and methods Destination: mk:H1_4 Children: Item: Title: Plasmids Destination: mk:H2_3 Item: Title: AAV vector production Destination: mk:H2_4 Item: Title: Mouse model Destination: mk:H2_5 Item: Title: In-vivo studies in mice Destination: mk:H2_6 Item: Title: Experiments in adult mice Destination: mk:H2_7 Item: Title: Grip test Destination: mk:H2_8 Item: Title: Anti-hGAA IgG measurement Destination: mk:H2_9 Item: Title: GAA activity and western blot analyses Destination: mk:H2_10 Item: Title: Glycogen content measurement Destination: mk:H2_11 Item: Title: Vector genome copy number Destination: mk:H2_12 Item: Title: Histology and staining Destination: mk:H2_13 Item: Title: Statistical analysis Destination: mk:H2_14 Item: Title: Data availability Destination: mk:H1_5 Item: Title: Acknowledgments Destination: mk:H1_6 Item: Title: Author contributions Destination: mk:H1_7 Item: Title: Declaration of interests Destination: mk:H1_8 Item: Title: Supplemental information Destination: falink9 Item: Title: References Destination: mk:HH2_1 Info: Title: A myotropic AAV vector combined with skeletal muscle cis-regulatory elements improve glycogen clearance in mouse models of Pompe disease Author: P. Sellier Subject: Molecular Therapy: Methods & Clinical Development, 33 (2025) 101464. doi:10.1016/j.omtm.2025.101464 Creator: PTC Arbortext Layout Developer 12.2.6665/W-x64 Producer: PDFlib+PDI 10.0.2p2 (C++/Win64) CreationDate: Mon Apr 28 07:55:04 CEST 2025 ModDate: Mon Apr 28 08:08:11 CEST 2025 ID: 0x87fc1160c7f65da05451a22fca4e37dd, 0x5f6982f68649be4c8a38d9f0b72cb1ce Filters: FilterPipeline: FlateDecode Images: Image: NisoImageMetadata: FormatName: image/png ImageWidth: 1575 ImageHeight: 637 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Interpolate: false Image: NisoImageMetadata: FormatName: image/png ImageWidth: 1385 ImageHeight: 2270 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Interpolate: false Image: NisoImageMetadata: FormatName: image/png ImageWidth: 1615 ImageHeight: 1975 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Interpolate: false Image: NisoImageMetadata: FormatName: image/png ImageWidth: 13 ImageHeight: 13 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Interpolate: false Image: NisoImageMetadata: FormatName: image/png ImageWidth: 1588 ImageHeight: 1000 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Interpolate: false Image: NisoImageMetadata: FormatName: image/png ImageWidth: 1576 ImageHeight: 604 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Interpolate: false Image: NisoImageMetadata: FormatName: image/png ImageWidth: 1503 ImageHeight: 362 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Interpolate: false Fonts: Type0: Font: BaseFont: BCDHEE+Calibri Encoding: Identity-H ToUnicode: true Font: BaseFont: PETNKE+TimesNewRomanPS-BoldMT Encoding: Identity-H ToUnicode: true Type1: Font: BaseFont: NXKVRV+MinionPro-Bold FontSubset: true FirstChar: 1 LastChar: 46 FontDescriptor: FontName: NXKVRV+MinionPro-Bold Flags: Nonsymbolic, ForceBold FontBBox: -318, -360, 1684, 917 FontFile3: true EncodingDictionary: BaseEncoding: WinAnsiEncoding Differences: true ToUnicode: true Font: BaseFont: CM_Maths_Symbols FirstChar: 1 LastChar: 138 FontDescriptor: FontName: CM_Maths_Symbols Flags: Symbolic FontBBox: -50, -180, 1000, 720 FontFile: true ToUnicode: true Font: BaseFont: HelveticaNeue-BoldItalic FirstChar: 32 LastChar: 251 FontDescriptor: FontName: HelveticaNeue-BoldItalic Flags: Symbolic, ForceBold FontBBox: -50, -180, 1000, 720 FontFile: true ToUnicode: true Font: BaseFont: HelveticaNeue-Italic FirstChar: 32 LastChar: 251 FontDescriptor: FontName: HelveticaNeue-Italic Flags: Symbolic FontBBox: -50, -180, 1000, 720 FontFile: true ToUnicode: true Font: BaseFont: DQGZZB+MinionPro-BoldIt FontSubset: true FirstChar: 1 LastChar: 8 FontDescriptor: FontName: DQGZZB+MinionPro-BoldIt Flags: Nonsymbolic, Italic, ForceBold FontBBox: -230, -360, 1684, 919 FontFile3: true EncodingDictionary: BaseEncoding: WinAnsiEncoding Differences: true ToUnicode: true Font: BaseFont: SNXVYO+STIX-Regular FontSubset: true FirstChar: 1 LastChar: 2 FontDescriptor: FontName: SNXVYO+STIX-Regular Flags: Nonsymbolic FontBBox: -970, -486, 2208, 1023 FontFile3: true EncodingDictionary: BaseEncoding: WinAnsiEncoding Differences: true ToUnicode: true Font: BaseFont: DTQHWI+MinionPro-It FontSubset: true FirstChar: 1 LastChar: 39 FontDescriptor: FontName: DTQHWI+MinionPro-It Flags: Nonsymbolic, Italic FontBBox: -201, -360, 1684, 919 FontFile3: true EncodingDictionary: BaseEncoding: WinAnsiEncoding Differences: true ToUnicode: true Font: BaseFont: HelveticaNeue-Light FirstChar: 32 LastChar: 251 FontDescriptor: FontName: HelveticaNeue-Light Flags: Symbolic FontBBox: -50, -180, 1000, 720 FontFile: true ToUnicode: true Font: BaseFont: ZWRFVC+STIX-Italic FontSubset: true FirstChar: 1 LastChar: 1 FontDescriptor: FontName: ZWRFVC+STIX-Italic Flags: Nonsymbolic, Italic FontBBox: -970, -305, 1429, 1023 FontFile3: true EncodingDictionary: BaseEncoding: WinAnsiEncoding Differences: true ToUnicode: true Font: BaseFont: HelveticaNeue-LightItalic FirstChar: 32 LastChar: 251 FontDescriptor: FontName: HelveticaNeue-LightItalic Flags: Symbolic FontBBox: -50, -180, 1000, 720 FontFile: true ToUnicode: true Font: BaseFont: HelveticaNeue-Roman FirstChar: 32 LastChar: 251 FontDescriptor: FontName: HelveticaNeue-Roman Flags: Symbolic FontBBox: -50, -180, 1000, 720 FontFile: true ToUnicode: true Font: BaseFont: YLUYDT+Rockwell FontSubset: true FirstChar: 1 LastChar: 1 FontDescriptor: FontName: YLUYDT+Rockwell Flags: Nonsymbolic FontBBox: -148, -223, 1054, 917 FontFile3: true EncodingDictionary: BaseEncoding: WinAnsiEncoding Differences: true ToUnicode: true Font: BaseFont: LEJJPM+MinionPro-Regular FontSubset: true FirstChar: 1 LastChar: 97 FontDescriptor: FontName: LEJJPM+MinionPro-Regular Flags: Nonsymbolic FontBBox: -289, -360, 1684, 917 FontFile3: true EncodingDictionary: BaseEncoding: WinAnsiEncoding Differences: true ToUnicode: true Font: BaseFont: TNHSPJ+Arial-BoldMT FontSubset: true FirstChar: 1 LastChar: 32 FontDescriptor: FontName: TNHSPJ+Arial-BoldMT Flags: Nonsymbolic, ForceBold FontBBox: -167, -250, 1006, 939 FontFile3: true EncodingDictionary: BaseEncoding: WinAnsiEncoding Differences: true ToUnicode: true Font: BaseFont: XAJJON+Arial-BoldItalicMT FontSubset: true FirstChar: 1 LastChar: 5 FontDescriptor: FontName: XAJJON+Arial-BoldItalicMT Flags: Nonsymbolic, Italic, ForceBold FontBBox: -248, -250, 1079, 944 FontFile3: true EncodingDictionary: BaseEncoding: WinAnsiEncoding Differences: true ToUnicode: true Font: BaseFont: YFGFQF+STIX-Bold FontSubset: true FirstChar: 1 LastChar: 1 FontDescriptor: FontName: YFGFQF+STIX-Bold Flags: Nonsymbolic, ForceBold FontBBox: -998, -552, 2000, 1055 FontFile3: true EncodingDictionary: BaseEncoding: WinAnsiEncoding Differences: true ToUnicode: true Font: BaseFont: HelveticaNeue-Bold FirstChar: 32 LastChar: 251 FontDescriptor: FontName: HelveticaNeue-Bold Flags: Symbolic, ForceBold FontBBox: -50, -180, 1000, 720 FontFile: true ToUnicode: true TrueType: Font: Name: F1 BaseFont: BCDEEE+Calibri FontSubset: true FirstChar: 32 LastChar: 177 FontDescriptor: FontName: BCDEEE+Calibri Flags: Nonsymbolic FontBBox: -503, -250, 1240, 750 FontFile2: true Encoding: WinAnsiEncoding Font: Name: F5 BaseFont: BCDIEE+Aptos FontSubset: true FirstChar: 36 LastChar: 36 FontDescriptor: FontName: BCDIEE+Aptos Flags: Nonsymbolic FontBBox: -500, -282, 1182, 939 FontFile2: true Encoding: WinAnsiEncoding Font: Name: F2 BaseFont: BCDFEE+Calibri-Bold FontSubset: true FirstChar: 32 LastChar: 181 FontDescriptor: FontName: BCDFEE+Calibri-Bold Flags: Nonsymbolic FontBBox: -519, -250, 1263, 750 FontFile2: true Encoding: WinAnsiEncoding Font: Name: F3 BaseFont: BCDGEE+Calibri-Italic FontSubset: true FirstChar: 32 LastChar: 115 FontDescriptor: FontName: BCDGEE+Calibri-Italic Flags: Nonsymbolic FontBBox: -725, -250, 1260, 750 FontFile2: true Encoding: WinAnsiEncoding CIDFontType2: Font: BaseFont: PETNKE+TimesNewRomanPS-BoldMT CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: PETNKE+TimesNewRomanPS-BoldMT Flags: Nonsymbolic, ForceBold FontBBox: -558, -307, 2000, 1026 FontFile2: true Font: BaseFont: BCDHEE+Calibri CIDSystemInfo: Registry: Adobe Registry: Identity Supplement: 0 FontDescriptor: FontName: BCDHEE+Calibri Flags: Nonsymbolic FontBBox: -503, -250, 1240, 750 FontFile2: true XMP: application/pdf doi:10.1016/j.omtm.2025.101464 A myotropic AAV vector combined with skeletal muscle cis-regulatory elements improve glycogen clearance in mouse models of Pompe disease P. Sellier F. Collaud Y. Krimi Benchekroun V. Jimenez X. Leon N. Daniele Q.H. Pham J. El Andari T. VandenDriessche M.K. Chuah D. Grimm F. Bosch F. Mingozzi G. Ronzitti Pompe disease AAV gene therapy muscle targeting liver detargeting immune response Molecular Therapy: Methods & Clinical Development, 33 (2025) 101464. doi:10.1016/j.omtm.2025.101464 The Author(s) journal Molecular Therapy: Methods & Clinical Development © 2025 The Author(s). Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy. 2329-0501 33 2 12 June 2025 2025-06-12 101464 101464 10.1016/j.omtm.2025.101464 https://doi.org/10.1016/j.omtm.2025.101464 2010-04-23 true 10.1016/j.omtm.2025.101464 elsevier.com sciencedirect.com VoR 7.0.1 10.1016/j.omtm.2025.101464 noindex 2010-04-23 true PStill version 1.84.42 sciencedirect.com elsevier.com PTC Arbortext Layout Developer 12.2.6665/W-x64 2025-04-28T10:55:04+05:30 2025-04-28T11:08:11+05:30 2025-04-28T11:08:11+05:30 True 1 https://www.elsevier.com/tdm/tdmrep-policy.json PDFlib+PDI 10.0.2p2 (C++/Win64) uuid:f0172705-a188-41bd-a9f8-6ed06d077826 uuid:58ce2daf-4048-4aa3-a30f-80c44d59ee9f http://creativecommons.org/licenses/by-nc-nd/4.0/ Pages: Page: Label: 1 Annotations: Annotation: Subtype: Link Rect: 48, 672, 48, 672 Flags: Print Annotation: Subtype: Link Rect: 90, 571, 95, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 95, 571, 101, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 101, 571, 105, 582 Flags: Print Destination: null Annotation: Subtype: Link Rect: 157, 571, 163, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 163, 571, 169, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 169, 571, 173, 582 Flags: Print Destination: null Annotation: Subtype: Link Rect: 279, 571, 285, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 285, 571, 289, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 343, 571, 347, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 388, 571, 392, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 445, 571, 451, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 451, 571, 455, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 511, 571, 514, 582 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 103, 557, 107, 568 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 203, 557, 207, 568 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 267, 557, 273, 568 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 273, 557, 277, 568 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 329, 557, 333, 568 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 377, 557, 380, 568 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 439, 557, 445, 568 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 445, 557, 449, 568 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 520, 557, 526, 568 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 526, 557, 530, 568 Flags: Print Destination: 1795 Annotation: Subtype: Link Rect: 342, 414, 345, 423 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 347, 414, 350, 423 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 430, 391, 433, 400 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 396, 357, 406, 366 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 438, 323, 441, 332 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 471, 254, 474, 263 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 363, 231, 367, 240 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 456, 208, 469, 217 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 382, 185, 398, 194 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 372, 151, 375, 160 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 377, 151, 383, 160 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 384, 151, 391, 160 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 308, 106, 441, 114 Flags: Print Annotation: Subtype: Link Rect: 333, 56, 400, 64 Flags: Print Annotation: Subtype: Link Rect: 48, 23, 64, 39 Flags: Print Page: Label: 2 Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 119, 606, 136, 615 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 129, 560, 146, 569 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 180, 537, 187, 546 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 67, 491, 73, 500 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 156, 446, 173, 454 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 104, 411, 120, 420 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 168, 400, 185, 409 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 83, 297, 99, 306 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 72, 274, 79, 283 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 148, 239, 154, 248 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 156, 239, 162, 248 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 132, 193, 139, 202 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 140, 193, 147, 202 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 164, 148, 171, 157 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 448, 514, 455, 523 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 408, 491, 414, 500 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 353, 434, 360, 443 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 361, 434, 368, 443 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 373, 434, 408, 443 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 397, 331, 427, 340 Flags: Print Destination: 4 Annotation: Subtype: Link Rect: 336, 285, 369, 294 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 409, 251, 442, 260 Flags: Print Destination: 4 Annotation: Subtype: Link Rect: 481, 251, 490, 260 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 499, 251, 529, 260 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 350, 205, 386, 214 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 398, 205, 431, 214 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 441, 182, 474, 191 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 484, 182, 515, 191 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 420, 136, 454, 145 Flags: Print Destination: 4 Annotation: Subtype: Link Rect: 481, 136, 489, 145 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 399, 90, 427, 99 Flags: Print Destination: 4 Page: Label: 3 Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 76, 56, 105, 65 Flags: Print Destination: 4 Annotation: Subtype: Link Rect: 531, 90, 553, 99 Flags: Print Destination: 21 Annotation: Subtype: Link Rect: 308, 79, 313, 88 Flags: Print Destination: 21 Annotation: Subtype: Link Rect: 513, 67, 543, 76 Flags: Print Destination: 21 Page: Label: 4 Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 118, 113, 147, 122 Flags: Print Destination: 21 Annotation: Subtype: Link Rect: 170, 90, 200, 99 Flags: Print Destination: 21 Annotation: Subtype: Link Rect: 372, 113, 381, 122 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 461, 67, 491, 76 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 495, 67, 532, 76 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 219, 156, 242, 163 Flags: Print Destination: 4 Page: Label: 5 Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 51, 640, 88, 649 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 248, 629, 283, 638 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 123, 594, 156, 603 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 66, 560, 73, 569 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 251, 526, 282, 535 Flags: Print Destination: 34 Annotation: Subtype: Link Rect: 99, 491, 129, 500 Flags: Print Destination: 34 Annotation: Subtype: Link Rect: 151, 468, 181, 477 Flags: Print Destination: 34 Annotation: Subtype: Link Rect: 231, 457, 265, 466 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 156, 411, 162, 420 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 164, 411, 170, 420 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 172, 411, 178, 420 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 180, 411, 186, 420 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 215, 377, 249, 386 Flags: Print Destination: 34 Annotation: Subtype: Link Rect: 275, 377, 283, 386 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 257, 354, 264, 363 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 217, 331, 250, 340 Flags: Print Destination: 34 Annotation: Subtype: Link Rect: 275, 331, 283, 340 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 51, 193, 85, 202 Flags: Print Destination: 34 Annotation: Subtype: Link Rect: 126, 193, 135, 202 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 259, 113, 265, 122 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 514, 652, 542, 661 Flags: Print Destination: 44 Annotation: Subtype: Link Rect: 530, 583, 554, 592 Flags: Print Destination: 44 Annotation: Subtype: Link Rect: 308, 572, 313, 580 Flags: Print Destination: 44 Annotation: Subtype: Link Rect: 351, 514, 381, 523 Flags: Print Destination: 44 Annotation: Subtype: Link Rect: 431, 434, 463, 443 Flags: Print Destination: 44 Annotation: Subtype: Link Rect: 334, 388, 366, 397 Flags: Print Destination: 44 Annotation: Subtype: Link Rect: 512, 239, 544, 248 Flags: Print Destination: 44 Annotation: Subtype: Link Rect: 312, 193, 344, 202 Flags: Print Destination: 44 Annotation: Subtype: Link Rect: 402, 159, 432, 168 Flags: Print Destination: 44 Annotation: Subtype: Link Rect: 387, 113, 422, 122 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 391, 90, 425, 99 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 447, 56, 478, 65 Flags: Print Destination: 67 Page: Label: 6 Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 101, 174, 131, 183 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 87, 163, 118, 172 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 387, 151, 394, 160 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 395, 151, 402, 160 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 403, 151, 410, 160 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 505, 71, 508, 79 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 509, 71, 516, 79 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 517, 71, 524, 79 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 525, 71, 532, 79 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 226, 235, 251, 242 Flags: Print Destination: 4 Page: Label: 7 Sequence: 7 Page: Label: 8 Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 106, 594, 113, 603 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 114, 594, 121, 603 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 104, 480, 110, 489 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 112, 480, 118, 489 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 199, 423, 205, 432 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 176, 354, 182, 363 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 184, 354, 200, 363 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 202, 354, 208, 363 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 210, 354, 216, 363 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 241, 319, 247, 328 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 249, 319, 255, 328 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 257, 319, 263, 328 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 142, 239, 148, 248 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 150, 239, 156, 248 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 126, 228, 133, 237 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 134, 228, 141, 237 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 411, 594, 417, 603 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 419, 594, 425, 603 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 428, 503, 434, 512 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 436, 503, 442, 512 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 444, 503, 450, 512 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 512, 491, 519, 500 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 355, 446, 362, 454 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 363, 446, 370, 454 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 506, 411, 522, 420 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 422, 319, 429, 328 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 530, 308, 537, 317 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 363, 251, 366, 260 Flags: Print Destination: 67 Annotation: Subtype: Link Rect: 368, 251, 374, 260 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 376, 251, 382, 260 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 370, 228, 376, 237 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 378, 228, 384, 237 Flags: Print Destination: 70 Page: Label: 9 Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 265, 617, 268, 626 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 270, 617, 276, 626 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 278, 617, 284, 626 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 151, 549, 158, 558 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 73, 514, 79, 523 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 81, 514, 87, 523 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 77, 491, 84, 500 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 85, 491, 92, 500 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 287, 285, 293, 294 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 279, 274, 285, 283 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 287, 274, 293, 283 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 224, 251, 231, 260 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 251, 216, 258, 225 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 115, 148, 122, 157 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 250, 125, 257, 134 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 172, 56, 178, 65 Flags: Print Destination: 73 Annotation: Subtype: Link Rect: 395, 652, 402, 661 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 467, 617, 474, 626 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 433, 331, 440, 340 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 422, 182, 429, 191 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 345, 79, 351, 88 Flags: Print Destination: 70 Page: Label: 10 Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 85, 503, 91, 512 Flags: Print Destination: 70 Annotation: Subtype: Link Rect: 450, 308, 554, 315 Flags: Print Annotation: Subtype: Link Rect: 308, 299, 328, 306 Flags: Print Annotation: Subtype: Link Rect: 483, 248, 554, 255 Flags: Print Annotation: Subtype: Link Rect: 320, 239, 369, 246 Flags: Print Annotation: Subtype: Link Rect: 487, 218, 554, 225 Flags: Print Annotation: Subtype: Link Rect: 320, 209, 373, 216 Flags: Print Annotation: Subtype: Link Rect: 337, 187, 471, 194 Flags: Print Annotation: Subtype: Link Rect: 333, 148, 446, 155 Flags: Print Annotation: Subtype: Link Rect: 320, 108, 457, 115 Flags: Print Annotation: Subtype: Link Rect: 419, 78, 531, 85 Flags: Print Page: Label: 11 Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 60, 656, 183, 663 Flags: Print Annotation: Subtype: Link Rect: 182, 617, 277, 624 Flags: Print Annotation: Subtype: Link Rect: 60, 605, 293, 612 Flags: Print Annotation: Subtype: Link Rect: 60, 596, 293, 603 Flags: Print Annotation: Subtype: Link Rect: 60, 587, 293, 594 Flags: Print Annotation: Subtype: Link Rect: 60, 578, 250, 585 Flags: Print Annotation: Subtype: Link Rect: 126, 539, 273, 546 Flags: Print Annotation: Subtype: Link Rect: 212, 500, 293, 507 Flags: Print Annotation: Subtype: Link Rect: 60, 491, 113, 498 Flags: Print Annotation: Subtype: Link Rect: 113, 451, 224, 458 Flags: Print Annotation: Subtype: Link Rect: 184, 412, 279, 419 Flags: Print Annotation: Subtype: Link Rect: 149, 373, 250, 380 Flags: Print Annotation: Subtype: Link Rect: 105, 334, 216, 341 Flags: Print Annotation: Subtype: Link Rect: 142, 295, 260, 302 Flags: Print Annotation: Subtype: Link Rect: 60, 247, 187, 254 Flags: Print Annotation: Subtype: Link Rect: 112, 207, 238, 214 Flags: Print Annotation: Subtype: Link Rect: 262, 186, 293, 193 Flags: Print Annotation: Subtype: Link Rect: 60, 177, 141, 184 Flags: Print Annotation: Subtype: Link Rect: 251, 156, 293, 163 Flags: Print Annotation: Subtype: Link Rect: 60, 147, 148, 154 Flags: Print Annotation: Subtype: Link Rect: 172, 126, 278, 133 Flags: Print Annotation: Subtype: Link Rect: 242, 105, 293, 112 Flags: Print Annotation: Subtype: Link Rect: 60, 96, 132, 103 Flags: Print Annotation: Subtype: Link Rect: 170, 56, 291, 63 Flags: Print Annotation: Subtype: Link Rect: 375, 638, 504, 645 Flags: Print Annotation: Subtype: Link Rect: 429, 599, 548, 606 Flags: Print Annotation: Subtype: Link Rect: 411, 559, 535, 566 Flags: Print Annotation: Subtype: Link Rect: 411, 520, 533, 527 Flags: Print Annotation: Subtype: Link Rect: 439, 490, 543, 497 Flags: Print Annotation: Subtype: Link Rect: 487, 450, 554, 457 Flags: Print Annotation: Subtype: Link Rect: 320, 441, 364, 448 Flags: Print Annotation: Subtype: Link Rect: 320, 402, 415, 409 Flags: Print Annotation: Subtype: Link Rect: 340, 354, 452, 361 Flags: Print Annotation: Subtype: Link Rect: 522, 323, 554, 330 Flags: Print Annotation: Subtype: Link Rect: 320, 314, 392, 321 Flags: Print Annotation: Subtype: Link Rect: 533, 284, 554, 291 Flags: Print Annotation: Subtype: Link Rect: 320, 275, 397, 282 Flags: Print Annotation: Subtype: Link Rect: 436, 235, 537, 242 Flags: Print Annotation: Subtype: Link Rect: 421, 205, 516, 212 Flags: Print Annotation: Subtype: Link Rect: 522, 166, 554, 173 Flags: Print Annotation: Subtype: Link Rect: 320, 157, 387, 164 Flags: Print Annotation: Subtype: Link Rect: 401, 117, 526, 124 Flags: Print Annotation: Subtype: Link Rect: 378, 78, 485, 85 Flags: Print Page: Label: 12 Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 189, 656, 293, 663 Flags: Print Annotation: Subtype: Link Rect: 60, 647, 78, 654 Flags: Print Annotation: Subtype: Link Rect: 124, 626, 246, 633 Flags: Print Annotation: Subtype: Link Rect: 131, 586, 237, 593 Flags: Print Annotation: Subtype: Link Rect: 94, 547, 208, 554 Flags: Print Annotation: Subtype: Link Rect: 148, 507, 273, 514 Flags: Print Annotation: Subtype: Link Rect: 251, 468, 293, 475 Flags: Print Annotation: Subtype: Link Rect: 60, 459, 126, 466 Flags: Print Annotation: Subtype: Link Rect: 115, 419, 244, 426 Flags: Print Annotation: Subtype: Link Rect: 131, 389, 211, 396 Flags: Print Annotation: Subtype: Link Rect: 60, 350, 183, 356 Flags: Print Annotation: Subtype: Link Rect: 84, 301, 206, 308 Flags: Print Annotation: Subtype: Link Rect: 170, 262, 292, 269 Flags: Print Annotation: Subtype: Link Rect: 131, 222, 237, 229 Flags: Print Annotation: Subtype: Link Rect: 251, 183, 293, 190 Flags: Print Annotation: Subtype: Link Rect: 60, 174, 139, 181 Flags: Print Annotation: Subtype: Link Rect: 188, 134, 292, 141 Flags: Print Annotation: Subtype: Link Rect: 60, 86, 155, 93 Flags: Print Annotation: Subtype: Link Rect: 320, 656, 421, 663 Flags: Print Annotation: Subtype: Link Rect: 354, 608, 487, 615 Flags: Print Annotation: Subtype: Link Rect: 439, 569, 552, 576 Flags: Print Annotation: Subtype: Link Rect: 320, 531, 443, 538 Flags: Print Annotation: Subtype: Link Rect: 357, 492, 450, 499 Flags: Print Annotation: Subtype: Link Rect: 357, 444, 470, 451 Flags: Print Annotation: Subtype: Link Rect: 522, 423, 554, 430 Flags: Print Annotation: Subtype: Link Rect: 320, 414, 413, 421 Flags: Print Annotation: Subtype: Link Rect: 320, 375, 442, 382 Flags: Print Annotation: Subtype: Link Rect: 427, 336, 547, 343 Flags: Print Annotation: Subtype: Link Rect: 393, 298, 524, 305 Flags: Print Annotation: Subtype: Link Rect: 465, 259, 554, 266 Flags: Print Annotation: Subtype: Link Rect: 320, 250, 355, 257 Flags: Print Annotation: Subtype: Link Rect: 407, 211, 527, 218 Flags: Print Annotation: Subtype: Link Rect: 430, 181, 521, 188 Flags: Print Annotation: Subtype: Link Rect: 483, 151, 554, 158 Flags: Print Annotation: Subtype: Link Rect: 320, 142, 378, 149 Flags: Print Annotation: Subtype: Link Rect: 477, 103, 554, 110 Flags: Print Annotation: Subtype: Link Rect: 320, 94, 345, 101 Flags: Print Annotation: Subtype: Link Rect: 320, 82, 554, 89 Flags: Print Annotation: Subtype: Link Rect: 320, 73, 554, 80 Flags: Print Annotation: Subtype: Link Rect: 320, 64, 521, 71 Flags: Print Page: Label: 12 Sequence: 13 Page: Label: 12 Sequence: 14 Page: Label: 12 Sequence: 15 Page: Label: 12 Sequence: 16 Page: Label: 12 Sequence: 17 Page: Label: 12 Sequence: 18 Page: Label: 12 Sequence: 19 Page: Label: 12 Sequence: 20 Page: Label: 12 Sequence: 21 Page: Label: 12 Sequence: 22 Page: Label: 12 Sequence: 23 Page: Label: 12 Sequence: 24 Checksum: 13502e89 Type: CRC32 Checksum: 6b644029b0d48b0344bb542c8a229580 Type: MD5 Checksum: 814f9f8e882aa9b68687f7173a3287bd803f0e08 Type: SHA-1 Checksum: ff38599da11e10fd0669e2f910586eca5050aa40d4d596324d319e41e5124b28 Type: SHA-256