0b3698e66a86a96280b66224292cbefc pmc_9940836.pdf 79a377e5a3ff90b6993aead7fbedf94133bc6ea6 pmc_9940836.pdf 203b046fc0f2978f8ed57813ca0c65126d29aacf58d8b205c62d69b30642c4bb pmc_9940836.pdf Title: Computational assessment of the impact of Cu(II) and Al(III) on β-amyloid42 fibrils: Binding sites, structural stability, and possible physiological implications Subject: One of Alzheimer’s disease major hallmarks is the aggregation of β-amyloid peptide, a process in which metal ions play an important role. Keywords: molecular modeling and simulation, molecular dynamic (MD), amyloid Aβ-42, protein-ligand docking, metal Author: Lorena Roldán-Martín Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.15 CreationDate: Tue Jan 31 11:30:24 2023 CET ModDate: Tue Jan 31 12:10:43 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3112538 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- HMDSGN+MinionPro-Regular Type 1 Custom yes yes no 37 0 QLCSTM+MuseoSans-700 Type 1 Custom yes yes no 38 0 VEXSWT+MuseoSans-300 Type 1 Custom yes yes no 39 0 QHWLRN+MTGU Type 1 Builtin yes yes no 44 0 PYLMQA+MuseoSans-300Italic Type 1 Custom yes yes no 45 0 VQWFHJ+MuseoSans-500 Type 1 Custom yes yes no 46 0 PJYUEC+MinionPro-Bold Type 1 Custom yes yes no 172 0 FWGGKP+MinionPro-It Type 1 Custom yes yes no 176 0 TUVPRG+MTSYN Type 1 Builtin yes yes no 181 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2023-12-16 02:30:19 CET RepresentationInformation: pmc_9940836.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-02 02:17:58 CET Size: 3112538 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 838 FreeObjects: 7 IncrementalUpdates: 1 DocumentCatalog: PageLayout: SinglePage PageMode: UseOutlines Outlines: Item: Title: Computational assessment of the impact of Cu(II) and Al(III) on β-amyloid42 fibrils: Binding sites, structural stability, and possible physiological implications Children: Item: Title: Introduction Item: Title: Materials and methods Children: Item: Title: Initial models Item: Title: Metal-binding areas: BioMetAll and GOLD Item: Title: Classical molecular dynamics simulations for metalloaggregates Item: Title: GaMDs simulations Item: Title: Analysis Item: Title: Results and discussion Children: Item: Title: Dynamical behavior of metal-free fibril Item: Title: Predicting metal-binding sites in amyloid aggregated structures Item: Title: GaMD of metal bound fibers Item: Title: Further analysis Item: Title: Conclusion Item: Title: Data availability statement Item: Title: Author contributions Item: Title: Funding Item: Title: Conflict of interest Item: Title: Publisher's note Item: Title: Supplementary material Item: Title: References Info: Title: Computational assessment of the impact of Cu(II) and Al(III) on β-amyloid42 fibrils: Binding sites, structural stability, and possible physiological implications Author: Lorena Roldán-Martín Subject: One of Alzheimer’s disease major hallmarks is the aggregation of β-amyloid peptide, a process in which metal ions play an important role. Keywords: molecular modeling and simulation, molecular dynamic (MD), amyloid Aβ-42, protein-ligand docking, metal Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.15 CreationDate: Tue Jan 31 12:00:24 CET 2023 ModDate: Tue Jan 31 12:40:43 CET 2023 ID: 0x5caa05a1c4c57c49c653ac80a4dec1fc, 0xbe527028995f564285f5ea7ae084f3f1 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: FWGGKP+MinionPro-It FontSubset: true FirstChar: 46 LastChar: 122 FontDescriptor: FontName: FWGGKP+MinionPro-It Flags: Symbolic FontBBox: -201, -360, 1684, 919 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: HMDSGN+MinionPro-Regular FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: HMDSGN+MinionPro-Regular Flags: Symbolic FontBBox: -289, -360, 1684, 917 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: TUVPRG+MTSYN FontSubset: true FirstChar: 0 LastChar: 67 FontDescriptor: FontName: TUVPRG+MTSYN Flags: Symbolic FontBBox: 0, -954, 1043, 900 FontFile: true Font: BaseFont: QLCSTM+MuseoSans-700 FontSubset: true FirstChar: 40 LastChar: 121 FontDescriptor: FontName: QLCSTM+MuseoSans-700 Flags: Symbolic FontBBox: -125, -210, 1126, 902 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: VEXSWT+MuseoSans-300 FontSubset: true FirstChar: 2 LastChar: 242 FontDescriptor: FontName: VEXSWT+MuseoSans-300 Flags: Symbolic FontBBox: -118, -210, 1088, 883 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QHWLRN+MTGU FontSubset: true FirstChar: 97 LastChar: 109 FontDescriptor: FontName: QHWLRN+MTGU Flags: Symbolic FontBBox: 25, -213, 839, 683 FontFile: true Font: BaseFont: PJYUEC+MinionPro-Bold FontSubset: true FirstChar: 44 LastChar: 150 FontDescriptor: FontName: PJYUEC+MinionPro-Bold Flags: Symbolic FontBBox: -318, -360, 1684, 917 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: PYLMQA+MuseoSans-300Italic FontSubset: true FirstChar: 46 LastChar: 117 FontDescriptor: FontName: PYLMQA+MuseoSans-300Italic Flags: Symbolic FontBBox: -245, -210, 1030, 883 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: VQWFHJ+MuseoSans-500 FontSubset: true FirstChar: 2 LastChar: 237 FontDescriptor: FontName: VQWFHJ+MuseoSans-500 Flags: Symbolic FontBBox: -121, -210, 1088, 892 FontFile: true EncodingDictionary: Differences: true XMP: molecular modeling and simulation, molecular dynamic (MD), amyloid Aβ-42, protein-ligand docking, metal pdfTeX-1.40.15 1.5 application/pdf fnins-17-1110311.tex Computational assessment of the impact of Cu(II) and Al(III) on β-amyloid42 fibrils: Binding sites, structural stability, and possible physiological implications One of Alzheimer’s disease major hallmarks is the aggregation of β-amyloid peptide, a process in which metal ions play an important role. Lorena Roldán-Martín Mariona Sodupe Jean-Didier Maréchal 2023-01-31T16:00:24+05:30 molecular modeling and simulation molecular dynamic (MD) amyloid Aβ-42 protein-ligand docking metal 2023-01-31T16:00:24+05:30 2023-01-31T16:40:43+05:30 2023-01-31T16:40:43+05:30 LaTeX with hyperref package uuid:20a333ef-dcef-47f2-b133-ea888200a820 uuid:18b9ede9-7569-4e91-a491-b072ac7ef1fe Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 41, 799, 230, 815 Annotation: Subtype: Link Rect: 440, 806, 521, 815 Annotation: Subtype: Link Rect: 440, 797, 539, 806 Annotation: Subtype: Link Rect: 440, 786, 549, 797 Annotation: Subtype: Link Rect: 41, 710, 118, 727 Annotation: Subtype: Link Rect: 55, 397, 145, 405 Annotation: Subtype: Link Rect: 94, 357, 122, 364 Annotation: Subtype: Link Rect: 122, 357, 158, 364 Annotation: Subtype: Link Rect: 158, 357, 194, 364 Annotation: Subtype: Link Rect: 41, 347, 67, 355 Annotation: Subtype: Link Rect: 67, 347, 93, 355 Annotation: Subtype: Link Rect: 207, 603, 553, 724 Annotation: Subtype: Link Rect: 230, 186, 255, 196 ActionDest: 699 Annotation: Subtype: Link Rect: 257, 186, 276, 196 ActionDest: 699 Annotation: Subtype: Link Rect: 346, 150, 397, 161 ActionDest: 661 Annotation: Subtype: Link Rect: 399, 150, 419, 161 ActionDest: 661 Annotation: Subtype: Link Rect: 464, 126, 485, 137 ActionDest: 661 Annotation: Subtype: Link Rect: 488, 126, 507, 137 ActionDest: 661 Annotation: Subtype: Link Rect: 510, 126, 553, 137 ActionDest: 661 Annotation: Subtype: Link Rect: 207, 114, 239, 125 ActionDest: 661 Annotation: Subtype: Link Rect: 243, 114, 262, 125 ActionDest: 661 Annotation: Subtype: Link Rect: 528, 90, 553, 101 ActionDest: 661 Annotation: Subtype: Link Rect: 207, 78, 255, 89 ActionDest: 661 Annotation: Subtype: Link Rect: 259, 78, 278, 89 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 78, 748, 133, 759 ActionDest: 661 Annotation: Subtype: Link Rect: 138, 748, 157, 759 ActionDest: 661 Annotation: Subtype: Link Rect: 106, 736, 167, 747 ActionDest: 661 Annotation: Subtype: Link Rect: 172, 736, 191, 747 ActionDest: 661 Annotation: Subtype: Link Rect: 76, 586, 97, 596 ActionDest: 661 Annotation: Subtype: Link Rect: 99, 586, 118, 596 ActionDest: 661 Annotation: Subtype: Link Rect: 245, 560, 289, 571 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 548, 60, 559 ActionDest: 661 Annotation: Subtype: Link Rect: 63, 548, 132, 559 ActionDest: 580 Annotation: Subtype: Link Rect: 135, 548, 154, 559 ActionDest: 580 Annotation: Subtype: Link Rect: 156, 548, 188, 559 ActionDest: 661 Annotation: Subtype: Link Rect: 190, 548, 209, 559 ActionDest: 661 Annotation: Subtype: Link Rect: 212, 548, 289, 559 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 535, 60, 546 ActionDest: 661 Annotation: Subtype: Link Rect: 64, 535, 120, 546 ActionDest: 661 Annotation: Subtype: Link Rect: 124, 535, 143, 546 ActionDest: 661 Annotation: Subtype: Link Rect: 269, 485, 291, 496 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 473, 94, 483 ActionDest: 661 Annotation: Subtype: Link Rect: 98, 473, 117, 483 ActionDest: 661 Annotation: Subtype: Link Rect: 120, 473, 165, 483 ActionDest: 661 Annotation: Subtype: Link Rect: 168, 473, 187, 483 ActionDest: 661 Annotation: Subtype: Link Rect: 191, 473, 248, 483 ActionDest: 699 Annotation: Subtype: Link Rect: 252, 473, 271, 483 ActionDest: 699 Annotation: Subtype: Link Rect: 86, 460, 125, 471 ActionDest: 661 Annotation: Subtype: Link Rect: 129, 460, 148, 471 ActionDest: 661 Annotation: Subtype: Link Rect: 152, 460, 191, 471 ActionDest: 661 Annotation: Subtype: Link Rect: 195, 460, 214, 471 ActionDest: 661 Annotation: Subtype: Link Rect: 217, 460, 266, 471 ActionDest: 661 Annotation: Subtype: Link Rect: 270, 460, 289, 471 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 449, 84, 458 ActionDest: 661 Annotation: Subtype: Link Rect: 86, 449, 106, 458 ActionDest: 661 Annotation: Subtype: Link Rect: 108, 449, 156, 458 ActionDest: 661 Annotation: Subtype: Link Rect: 159, 449, 178, 458 ActionDest: 661 Annotation: Subtype: Link Rect: 180, 449, 289, 458 ActionDest: 699 Annotation: Subtype: Link Rect: 41, 435, 60, 446 ActionDest: 699 Annotation: Subtype: Link Rect: 63, 435, 110, 446 ActionDest: 699 Annotation: Subtype: Link Rect: 113, 435, 132, 446 ActionDest: 699 Annotation: Subtype: Link Rect: 134, 435, 189, 446 ActionDest: 661 Annotation: Subtype: Link Rect: 191, 435, 211, 446 ActionDest: 661 Annotation: Subtype: Link Rect: 213, 435, 289, 446 ActionDest: 699 Annotation: Subtype: Link Rect: 41, 423, 60, 433 ActionDest: 699 Annotation: Subtype: Link Rect: 260, 360, 291, 371 ActionDest: 699 Annotation: Subtype: Link Rect: 41, 348, 87, 358 ActionDest: 699 Annotation: Subtype: Link Rect: 89, 348, 109, 358 ActionDest: 699 Annotation: Subtype: Link Rect: 238, 310, 262, 320 ActionDest: 661 Annotation: Subtype: Link Rect: 267, 310, 286, 320 ActionDest: 661 Annotation: Subtype: Link Rect: 124, 285, 194, 295 ActionDest: 661 Annotation: Subtype: Link Rect: 196, 285, 216, 295 ActionDest: 661 Annotation: Subtype: Link Rect: 109, 222, 147, 233 ActionDest: 699 Annotation: Subtype: Link Rect: 150, 222, 169, 233 ActionDest: 699 Annotation: Subtype: Link Rect: 172, 222, 213, 233 ActionDest: 699 Annotation: Subtype: Link Rect: 216, 222, 235, 233 ActionDest: 699 Annotation: Subtype: Link Rect: 237, 222, 289, 233 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 209, 60, 220 ActionDest: 661 Annotation: Subtype: Link Rect: 62, 209, 108, 220 ActionDest: 661 Annotation: Subtype: Link Rect: 110, 209, 129, 220 ActionDest: 661 Annotation: Subtype: Link Rect: 137, 147, 224, 157 ActionDest: 699 Annotation: Subtype: Link Rect: 228, 147, 247, 157 ActionDest: 699 Annotation: Subtype: Link Rect: 256, 122, 291, 132 ActionDest: 699 Annotation: Subtype: Link Rect: 41, 109, 61, 120 ActionDest: 699 Annotation: Subtype: Link Rect: 64, 109, 84, 120 ActionDest: 699 Annotation: Subtype: Link Rect: 313, 722, 346, 732 ActionDest: 238 Annotation: Subtype: Link Rect: 353, 640, 396, 650 ActionDest: 699 Annotation: Subtype: Link Rect: 399, 640, 419, 650 ActionDest: 699 Annotation: Subtype: Link Rect: 358, 592, 401, 603 ActionDest: 699 Annotation: Subtype: Link Rect: 406, 592, 426, 603 ActionDest: 699 Annotation: Subtype: Link Rect: 518, 521, 553, 532 ActionDest: 661 Annotation: Subtype: Link Rect: 303, 509, 325, 520 ActionDest: 661 Annotation: Subtype: Link Rect: 330, 509, 349, 520 ActionDest: 661 Annotation: Subtype: Link Rect: 377, 486, 424, 496 ActionDest: 661 Annotation: Subtype: Link Rect: 429, 486, 448, 496 ActionDest: 661 Annotation: Subtype: Link Rect: 444, 379, 486, 389 ActionDest: 661 Annotation: Subtype: Link Rect: 491, 379, 510, 389 ActionDest: 661 Annotation: Subtype: Link Rect: 381, 261, 468, 271 ActionDest: 699 Annotation: Subtype: Link Rect: 472, 261, 491, 271 ActionDest: 699 Annotation: Subtype: Link Rect: 509, 178, 551, 188 ActionDest: 661 Annotation: Subtype: Link Rect: 303, 166, 323, 176 ActionDest: 661 Annotation: Subtype: Link Rect: 444, 166, 489, 176 ActionDest: 661 Annotation: Subtype: Link Rect: 494, 166, 513, 176 ActionDest: 661 Annotation: Subtype: Link Rect: 494, 142, 551, 153 ActionDest: 699 Annotation: Subtype: Link Rect: 303, 130, 323, 141 ActionDest: 699 Annotation: Subtype: Link Rect: 423, 83, 551, 93 ActionDest: 661 Annotation: Subtype: Link Rect: 303, 71, 323, 82 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 44, 96, 94, 106 ActionDest: 661 Annotation: Subtype: Link Rect: 98, 96, 117, 106 ActionDest: 661 Annotation: Subtype: Link Rect: 98, 83, 134, 94 ActionDest: 661 Annotation: Subtype: Link Rect: 137, 83, 156, 94 ActionDest: 661 Annotation: Subtype: Link Rect: 159, 83, 183, 94 ActionDest: 580 Annotation: Subtype: Link Rect: 186, 83, 205, 94 ActionDest: 580 Annotation: Subtype: Link Rect: 153, 71, 207, 82 ActionDest: 661 Annotation: Subtype: Link Rect: 210, 71, 229, 82 ActionDest: 661 Annotation: Subtype: Link Rect: 306, 148, 368, 159 ActionDest: 661 Annotation: Subtype: Link Rect: 375, 148, 394, 159 ActionDest: 661 Annotation: Subtype: Link Rect: 444, 110, 491, 121 ActionDest: 661 Annotation: Subtype: Link Rect: 495, 110, 514, 121 ActionDest: 661 Annotation: Subtype: Link Rect: 448, 85, 504, 95 ActionDest: 661 Annotation: Subtype: Link Rect: 506, 85, 526, 95 ActionDest: 661 Annotation: Subtype: Link Rect: 490, 60, 529, 70 ActionDest: 699 Annotation: Subtype: Link Rect: 531, 60, 550, 70 ActionDest: 699 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 152, 749, 193, 760 ActionDest: 580 Annotation: Subtype: Link Rect: 195, 749, 214, 760 ActionDest: 580 Annotation: Subtype: Link Rect: 85, 725, 124, 736 ActionDest: 661 Annotation: Subtype: Link Rect: 127, 725, 146, 736 ActionDest: 661 Annotation: Subtype: Link Rect: 246, 725, 289, 736 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 713, 60, 724 ActionDest: 661 Annotation: Subtype: Link Rect: 143, 690, 203, 701 ActionDest: 661 Annotation: Subtype: Link Rect: 206, 690, 225, 701 ActionDest: 661 Annotation: Subtype: Link Rect: 100, 630, 148, 641 ActionDest: 661 Annotation: Subtype: Link Rect: 151, 630, 171, 641 ActionDest: 661 Annotation: Subtype: Link Rect: 118, 618, 180, 629 ActionDest: 661 Annotation: Subtype: Link Rect: 182, 618, 202, 629 ActionDest: 661 Annotation: Subtype: Link Rect: 44, 607, 100, 617 ActionDest: 699 Annotation: Subtype: Link Rect: 104, 607, 123, 617 ActionDest: 699 Annotation: Subtype: Link Rect: 245, 476, 289, 487 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 465, 60, 475 ActionDest: 661 Annotation: Subtype: Link Rect: 178, 346, 231, 356 ActionDest: 661 Annotation: Subtype: Link Rect: 233, 346, 252, 356 ActionDest: 661 Annotation: Subtype: Link Rect: 254, 346, 274, 356 ActionDest: 661 Annotation: Subtype: Link Rect: 195, 250, 237, 261 ActionDest: 699 Annotation: Subtype: Link Rect: 240, 250, 259, 261 ActionDest: 699 Annotation: Subtype: Link Rect: 178, 155, 241, 166 ActionDest: 661 Annotation: Subtype: Link Rect: 244, 155, 263, 166 ActionDest: 661 Annotation: Subtype: Link Rect: 267, 155, 291, 166 ActionDest: 580 Annotation: Subtype: Link Rect: 41, 143, 61, 154 ActionDest: 580 Annotation: Subtype: Link Rect: 64, 143, 83, 154 ActionDest: 580 Annotation: Subtype: Link Rect: 306, 642, 376, 653 ActionDest: 661 Annotation: Subtype: Link Rect: 378, 642, 397, 653 ActionDest: 661 Annotation: Subtype: Link Rect: 399, 642, 438, 653 ActionDest: 372 Annotation: Subtype: Link Rect: 430, 547, 487, 557 ActionDest: 372 Annotation: Subtype: Link Rect: 411, 535, 510, 545 ActionDest: 580 Annotation: Subtype: Link Rect: 306, 475, 345, 486 ActionDest: 372 Annotation: Subtype: Link Rect: 359, 439, 399, 450 ActionDest: 372 Annotation: Subtype: Link Rect: 317, 428, 365, 438 ActionDest: 661 Annotation: Subtype: Link Rect: 371, 428, 390, 438 ActionDest: 661 Annotation: Subtype: Link Rect: 399, 178, 440, 189 ActionDest: 372 Annotation: Subtype: Link Rect: 503, 166, 551, 177 ActionDest: 699 Annotation: Subtype: Link Rect: 303, 154, 323, 165 ActionDest: 699 Annotation: Subtype: Link Rect: 372, 130, 410, 141 ActionDest: 372 Annotation: Subtype: Link Rect: 306, 83, 344, 93 ActionDest: 372 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 189, 498, 221, 506 ActionDest: 699 Annotation: Subtype: Link Rect: 223, 498, 240, 506 ActionDest: 699 Annotation: Subtype: Link Rect: 167, 323, 189, 333 ActionDest: 661 Annotation: Subtype: Link Rect: 193, 323, 212, 333 ActionDest: 661 Annotation: Subtype: Link Rect: 216, 323, 266, 333 ActionDest: 661 Annotation: Subtype: Link Rect: 270, 323, 289, 333 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 310, 85, 321 ActionDest: 661 Annotation: Subtype: Link Rect: 87, 310, 107, 321 ActionDest: 661 Annotation: Subtype: Link Rect: 110, 310, 187, 321 ActionDest: 699 Annotation: Subtype: Link Rect: 190, 310, 209, 321 ActionDest: 699 Annotation: Subtype: Link Rect: 212, 310, 236, 321 ActionDest: 661 Annotation: Subtype: Link Rect: 239, 310, 258, 321 ActionDest: 661 Annotation: Subtype: Link Rect: 239, 286, 289, 297 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 274, 60, 285 ActionDest: 661 Annotation: Subtype: Link Rect: 169, 274, 241, 285 ActionDest: 661 Annotation: Subtype: Link Rect: 243, 274, 262, 285 ActionDest: 661 Annotation: Subtype: Link Rect: 181, 71, 265, 82 ActionDest: 699 Annotation: Subtype: Link Rect: 267, 71, 286, 82 ActionDest: 699 Annotation: Subtype: Link Rect: 422, 362, 484, 372 ActionDest: 580 Annotation: Subtype: Link Rect: 487, 362, 506, 372 ActionDest: 580 Annotation: Subtype: Link Rect: 510, 362, 529, 372 ActionDest: 580 Annotation: Subtype: Link Rect: 365, 277, 416, 288 ActionDest: 661 Annotation: Subtype: Link Rect: 419, 277, 439, 288 ActionDest: 661 Annotation: Subtype: Link Rect: 306, 216, 377, 227 ActionDest: 661 Annotation: Subtype: Link Rect: 380, 216, 399, 227 ActionDest: 661 Annotation: Subtype: Link Rect: 372, 132, 413, 142 ActionDest: 423 Annotation: Subtype: Link Rect: 335, 107, 374, 118 ActionDest: 423 Annotation: Subtype: Link Rect: 303, 95, 343, 106 ActionDest: 699 Annotation: Subtype: Link Rect: 346, 95, 365, 106 ActionDest: 699 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 138, 423, 192, 433 ActionDest: 423 Annotation: Subtype: Link Rect: 258, 251, 291, 262 ActionDest: 454 Annotation: Subtype: Link Rect: 59, 239, 154, 250 ActionDest: 580 Annotation: Subtype: Link Rect: 172, 227, 212, 238 ActionDest: 454 Annotation: Subtype: Link Rect: 232, 227, 291, 238 ActionDest: 580 Annotation: Subtype: Link Rect: 41, 215, 97, 226 ActionDest: 580 Annotation: Subtype: Link Rect: 44, 203, 85, 214 ActionDest: 454 Annotation: Subtype: Link Rect: 125, 179, 170, 190 ActionDest: 661 Annotation: Subtype: Link Rect: 173, 179, 192, 190 ActionDest: 661 Annotation: Subtype: Link Rect: 79, 155, 119, 166 ActionDest: 454 Annotation: Subtype: Link Rect: 210, 59, 289, 70 ActionDest: 699 Annotation: Subtype: Link Rect: 41, 47, 60, 58 ActionDest: 699 Annotation: Subtype: Link Rect: 412, 398, 451, 409 ActionDest: 454 Annotation: Subtype: Link Rect: 442, 351, 480, 361 ActionDest: 454 Annotation: Subtype: Link Rect: 480, 290, 521, 301 ActionDest: 454 Annotation: Subtype: Link Rect: 439, 266, 478, 277 ActionDest: 454 Annotation: Subtype: Link Rect: 494, 266, 553, 277 ActionDest: 580 Annotation: Subtype: Link Rect: 303, 254, 339, 265 ActionDest: 580 Annotation: Subtype: Link Rect: 347, 242, 387, 253 ActionDest: 454 Annotation: Subtype: Link Rect: 402, 231, 443, 241 ActionDest: 454 Annotation: Subtype: Link Rect: 493, 183, 548, 193 ActionDest: 454 Annotation: Subtype: Link Rect: 424, 135, 462, 145 ActionDest: 454 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 117, 72, 214, 83 ActionDest: 580 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 129, 371, 169, 382 ActionDest: 502 Annotation: Subtype: Link Rect: 63, 323, 102, 334 ActionDest: 502 Annotation: Subtype: Link Rect: 196, 287, 235, 298 ActionDest: 502 Annotation: Subtype: Link Rect: 130, 251, 170, 262 ActionDest: 502 Annotation: Subtype: Link Rect: 176, 215, 209, 226 ActionDest: 531 Annotation: Subtype: Link Rect: 193, 158, 232, 169 ActionDest: 502 Annotation: Subtype: Link Rect: 218, 121, 257, 131 ActionDest: 502 Annotation: Subtype: Link Rect: 457, 392, 496, 403 ActionDest: 502 Annotation: Subtype: Link Rect: 358, 237, 398, 248 ActionDest: 502 Annotation: Subtype: Link Rect: 360, 214, 393, 224 ActionDest: 531 Annotation: Subtype: Link Rect: 441, 71, 476, 82 ActionDest: 531 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 44, 135, 80, 145 ActionDest: 531 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 273, 525, 291, 536 ActionDest: 661 Annotation: Subtype: Link Rect: 41, 512, 62, 523 ActionDest: 661 Annotation: Subtype: Link Rect: 66, 512, 85, 523 ActionDest: 661 Annotation: Subtype: Link Rect: 191, 512, 251, 523 ActionDest: 661 Annotation: Subtype: Link Rect: 255, 512, 274, 523 ActionDest: 661 Annotation: Subtype: Link Rect: 175, 408, 220, 418 ActionDest: 661 Annotation: Subtype: Link Rect: 222, 408, 241, 418 ActionDest: 661 Annotation: Subtype: Link Rect: 62, 381, 108, 392 ActionDest: 699 Annotation: Subtype: Link Rect: 112, 381, 131, 392 ActionDest: 699 Annotation: Subtype: Link Rect: 44, 356, 87, 366 ActionDest: 661 Annotation: Subtype: Link Rect: 89, 356, 109, 366 ActionDest: 661 Annotation: Subtype: Link Rect: 89, 263, 145, 274 ActionDest: 661 Annotation: Subtype: Link Rect: 150, 263, 169, 274 ActionDest: 661 Annotation: Subtype: Link Rect: 359, 722, 454, 733 ActionDest: 580 Annotation: Subtype: Link Rect: 317, 223, 553, 234 Annotation: Subtype: Link Rect: 303, 211, 409, 222 Annotation: Subtype: Link Rect: 147, 119, 213, 128 Annotation: Subtype: Link Rect: 203, 90, 271, 99 Annotation: Subtype: Link Rect: 124, 70, 218, 79 Annotation: Subtype: Link Rect: 470, 127, 553, 136 Annotation: Subtype: Link Rect: 312, 121, 324, 128 Annotation: Subtype: Link Rect: 446, 91, 519, 99 Annotation: Subtype: Link Rect: 399, 70, 463, 78 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 196, 746, 291, 754 Annotation: Subtype: Link Rect: 50, 739, 69, 746 Annotation: Subtype: Link Rect: 213, 708, 291, 717 Annotation: Subtype: Link Rect: 50, 702, 62, 708 Annotation: Subtype: Link Rect: 77, 664, 146, 672 Annotation: Subtype: Link Rect: 42, 637, 135, 644 Annotation: Subtype: Link Rect: 42, 588, 106, 597 Annotation: Subtype: Link Rect: 213, 568, 291, 577 Annotation: Subtype: Link Rect: 50, 561, 63, 568 Annotation: Subtype: Link Rect: 251, 540, 291, 549 Annotation: Subtype: Link Rect: 50, 534, 73, 540 Annotation: Subtype: Link Rect: 135, 512, 239, 521 Annotation: Subtype: Link Rect: 235, 484, 291, 493 Annotation: Subtype: Link Rect: 50, 477, 92, 485 Annotation: Subtype: Link Rect: 268, 456, 291, 465 Annotation: Subtype: Link Rect: 50, 450, 103, 457 Annotation: Subtype: Link Rect: 279, 428, 291, 437 Annotation: Subtype: Link Rect: 50, 422, 96, 429 Annotation: Subtype: Link Rect: 165, 392, 232, 401 Annotation: Subtype: Link Rect: 60, 364, 146, 373 Annotation: Subtype: Link Rect: 137, 345, 220, 353 Annotation: Subtype: Link Rect: 113, 325, 216, 334 Annotation: Subtype: Link Rect: 209, 297, 291, 306 Annotation: Subtype: Link Rect: 50, 290, 68, 298 Annotation: Subtype: Link Rect: 238, 261, 291, 270 Annotation: Subtype: Link Rect: 50, 254, 74, 261 Annotation: Subtype: Link Rect: 42, 225, 148, 233 Annotation: Subtype: Link Rect: 42, 196, 123, 204 Annotation: Subtype: Link Rect: 80, 167, 143, 176 Annotation: Subtype: Link Rect: 42, 139, 118, 147 Annotation: Subtype: Link Rect: 76, 118, 143, 126 Annotation: Subtype: Link Rect: 77, 89, 163, 98 Annotation: Subtype: Link Rect: 145, 61, 242, 69 Annotation: Subtype: Link Rect: 422, 746, 523, 754 Annotation: Subtype: Link Rect: 327, 718, 413, 727 Annotation: Subtype: Link Rect: 421, 698, 507, 707 Annotation: Subtype: Link Rect: 369, 671, 447, 679 Annotation: Subtype: Link Rect: 541, 642, 553, 651 Annotation: Subtype: Link Rect: 312, 635, 388, 642 Annotation: Subtype: Link Rect: 418, 606, 497, 615 Annotation: Subtype: Link Rect: 515, 578, 553, 586 Annotation: Subtype: Link Rect: 312, 570, 351, 578 Annotation: Subtype: Link Rect: 304, 534, 371, 542 Annotation: Subtype: Link Rect: 383, 505, 494, 514 Annotation: Subtype: Link Rect: 479, 485, 553, 494 Annotation: Subtype: Link Rect: 312, 479, 342, 486 Annotation: Subtype: Link Rect: 394, 449, 478, 458 Annotation: Subtype: Link Rect: 471, 429, 553, 438 Annotation: Subtype: Link Rect: 312, 422, 328, 429 Annotation: Subtype: Link Rect: 304, 393, 390, 402 Annotation: Subtype: Link Rect: 486, 373, 553, 382 Annotation: Subtype: Link Rect: 312, 367, 324, 373 Annotation: Subtype: Link Rect: 345, 330, 421, 338 Annotation: Subtype: Link Rect: 304, 302, 408, 310 Annotation: Subtype: Link Rect: 515, 281, 553, 290 Annotation: Subtype: Link Rect: 312, 273, 334, 281 Annotation: Subtype: Link Rect: 332, 245, 401, 254 Annotation: Subtype: Link Rect: 304, 209, 370, 217 Annotation: Subtype: Link Rect: 502, 180, 553, 189 Annotation: Subtype: Link Rect: 312, 174, 319, 181 Annotation: Subtype: Link Rect: 358, 144, 444, 153 Annotation: Subtype: Link Rect: 440, 116, 549, 125 Annotation: Subtype: Link Rect: 505, 96, 553, 105 Annotation: Subtype: Link Rect: 312, 90, 319, 96 Annotation: Subtype: Link Rect: 398, 60, 463, 69 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 462, 806, 553, 814 Annotation: Subtype: Link Rect: 148, 746, 225, 754 Annotation: Subtype: Link Rect: 158, 717, 261, 726 Annotation: Subtype: Link Rect: 279, 689, 292, 698 Annotation: Subtype: Link Rect: 50, 681, 115, 690 Annotation: Subtype: Link Rect: 225, 654, 289, 662 Annotation: Subtype: Link Rect: 177, 634, 292, 642 Annotation: Subtype: Link Rect: 50, 626, 141, 634 Annotation: Subtype: Link Rect: 42, 591, 128, 599 Annotation: Subtype: Link Rect: 243, 562, 292, 571 Annotation: Subtype: Link Rect: 50, 554, 82, 563 Annotation: Subtype: Link Rect: 500, 754, 553, 762 Annotation: Subtype: Link Rect: 312, 747, 319, 754 Annotation: Subtype: Link Rect: 476, 718, 553, 727 Annotation: Subtype: Link Rect: 312, 711, 322, 718 Annotation: Subtype: Link Rect: 399, 682, 499, 691 Annotation: Subtype: Link Rect: 407, 653, 493, 662 Annotation: Subtype: Link Rect: 376, 617, 479, 626 Annotation: Subtype: Link Rect: 497, 590, 553, 598 Annotation: Subtype: Link Rect: 312, 583, 319, 590 Annotation: Subtype: Link Rect: 332, 555, 418, 563 Annotation: Subtype: Link Rect: 41, 26, 126, 34 Annotation: Subtype: Link Rect: 505, 26, 553, 34 Checksum: e5931f62 Type: CRC32 Checksum: 0b3698e66a86a96280b66224292cbefc Type: MD5 Checksum: 79a377e5a3ff90b6993aead7fbedf94133bc6ea6 Type: SHA-1 Checksum: 203b046fc0f2978f8ed57813ca0c65126d29aacf58d8b205c62d69b30642c4bb Type: SHA-256