9a57f65a52fff8681e4a5a8897aadec9 Nan_a2023v13p1619.pdf 843c1baf320bbf903b69a7d57c8b1a0320dd1d3a Nan_a2023v13p1619.pdf 826f1a0e4fa591fd6d13aea55c87e52202b567292c56be55496b02735ec8e5d1 Nan_a2023v13p1619.pdf Title: Platinum-Based Nanoformulations for Glioblastoma Treatment: The Resurgence of Platinum Drugs? Subject: Current therapies for treating Glioblastoma (GB), and brain tumours in general, are inefficient and represent numerous challenges. In addition to surgical resection, chemotherapy and radiotherapy are presently used as standards of care. However, treated patients still face a dismal prognosis with a median survival below 15–18 months. Temozolomide (TMZ) is the main chemotherapeutic agent administered; however, intrinsic or acquired resistance to TMZ contributes to the limited efficacy of this drug. To circumvent the current drawbacks in GB treatment, a large number of classical and non-classical platinum complexes have been prepared and tested for anticancer activity, especially platinum (IV)-based prodrugs. Platinum complexes, used as alkylating agents in the anticancer chemotherapy of some malignancies, are though often associated with severe systemic toxicity (i.e., neurotoxicity), especially after long-term treatments. The objective of the current developments is to produce novel nanoformulations with improved lipophilicity and passive diffusion, promoting intracellular accumulation, while reducing toxicity and optimizing the concomitant treatment of chemo-/radiotherapy. Moreover, the blood–brain barrier (BBB) prevents the access of the drugs to the brain and accumulation in tumour cells, so it represents a key challenge for GB management. The development of novel nanomedicines with the ability to (i) encapsulate Pt-based drugs and pro-drugs, (ii) cross the BBB, and (iii) specifically target cancer cells represents a promising approach to increase the therapeutic effect of the anticancer drugs and reduce undesired side effects. In this review, a critical discussion is presented concerning different families of nanoparticles able to encapsulate platinum anticancer drugs and their application for GB treatment, emphasizing their potential for increasing the effectiveness of platinum-based drugs. Keywords: glioblastoma; platinum drugs; nanoformulation; chemotherapy; brain tumours Author: Paula Alfonso-Triguero, Julia Lorenzo, Ana Paula Candiota, Carles Arús, Daniel Ruiz-Molina and Fernando Novio Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri May 12 08:07:28 2023 CEST ModDate: Fri May 12 08:09:38 2023 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 32 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 3998316 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ENLEMO+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 MWHIBA+VnURWPalladioL Type 1 Custom yes yes no 15 0 BZPZJK+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 DTVAIO+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 JEAHRS+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 NPLVPL+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 46 0 NOVUER+EURM10 Type 1 Builtin yes yes no 74 0 BDEPMK+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 85 0 BDEPNL+PalatinoLinotype CID TrueType Identity-H yes yes yes 88 0 BDEPNM+PalatinoLinotype TrueType WinAnsi yes yes no 94 0 BDEPNO+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 97 0 BDFBDG+PalatinoLinotype TrueType MacRoman yes yes no 100 0 BDEPMK+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 120 0 BDEPNL+PalatinoLinotype CID TrueType Identity-H yes yes yes 123 0 BDEPNM+PalatinoLinotype TrueType WinAnsi yes yes no 129 0 BDEPNO+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 132 0 BDFBDG+PalatinoLinotype TrueType MacRoman yes yes no 135 0 BDEPMK+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 152 0 BDEPNL+PalatinoLinotype CID TrueType Identity-H yes yes yes 155 0 BDEPNM+PalatinoLinotype TrueType WinAnsi yes yes no 161 0 BDEPNO+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 164 0 BDFBDG+PalatinoLinotype TrueType MacRoman yes yes no 167 0 BDFGIH+Symbol Type 1C Custom yes yes yes 188 0 BDEPMK+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 193 0 BDEPNL+PalatinoLinotype CID TrueType Identity-H yes yes yes 196 0 BDEPNM+PalatinoLinotype TrueType WinAnsi yes yes no 202 0 BDEPNO+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 205 0 BDFBDG+PalatinoLinotype TrueType MacRoman yes yes no 208 0 BDFGKI+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 211 0 BDEPMK+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 225 0 BDEPNL+PalatinoLinotype CID TrueType Identity-H yes yes yes 228 0 BDEPNM+PalatinoLinotype TrueType WinAnsi yes yes no 234 0 BDEPNO+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 237 0 BDFBDG+PalatinoLinotype TrueType MacRoman yes yes no 240 0 BDFGKI+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 243 0 TAQQTO+CMSY10 Type 1 Builtin yes yes no 253 0 BDEPMK+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 264 0 BDEPNL+PalatinoLinotype CID TrueType Identity-H yes yes yes 267 0 BDEPNM+PalatinoLinotype TrueType WinAnsi yes yes no 273 0 BDEPNO+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 276 0 BDFBDG+PalatinoLinotype TrueType MacRoman yes yes no 279 0 BDFGKI+PalatinoLinotype,BoldItalic TrueType WinAnsi yes yes no 282 0 BDEPMK+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 296 0 BDEPNM+PalatinoLinotype TrueType WinAnsi yes yes no 299 0 BDEPNO+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 302 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-09-27 02:36:37 CEST RepresentationInformation: Nan_a2023v13p1619.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-09-26 19:35:50 CEST Size: 3998316 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 925 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Item: Title: Current Landscape for GB Treatment Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Platinum and Glioblastoma: State-of-the-Art Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Platinum-Based Drugs Limitations and Opportunities Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Children: Item: Title: Factors Related to Brain Uptake Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Narrow Therapeutic Window Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: Inappropriate Dosing Schedule Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Item: Title: Extensive Off-Target Toxicity Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1a3869f4 Item: Title: Sequestering/Deactivating Reactions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@a38d7a3 Item: Title: Platinum-Based Drugs Limitations and Opportunities Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77f99a05 Children: Item: Title: Cisplatin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@63440df3 Item: Title: Carboplatin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@3aeaafa6 Item: Title: Oxaliplatin Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@76a3e297 Item: Title: Pt(IV) Prodrugs Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Why Repurpose Platinum Drugs and Use Nanotechnology? Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Item: Title: Summary and Future Perspectives Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Info: Title: Platinum-Based Nanoformulations for Glioblastoma Treatment: The Resurgence of Platinum Drugs? Author: Paula Alfonso-Triguero, Julia Lorenzo, Ana Paula Candiota, Carles Arús, Daniel Ruiz-Molina and Fernando Novio Subject: Current therapies for treating Glioblastoma (GB), and brain tumours in general, are inefficient and represent numerous challenges. In addition to surgical resection, chemotherapy and radiotherapy are presently used as standards of care. However, treated patients still face a dismal prognosis with a median survival below 15 18 months. Temozolomide (TMZ) is the main chemotherapeutic agent administered; however, intrinsic or acquired resistance to TMZ contributes to the limited efficacy of this drug. To circumvent the current drawbacks in GB treatment, a large number of classical and non-classical platinum complexes have been prepared and tested for anticancer activity, especially platinum (IV)-based prodrugs. Platinum complexes, used as alkylating agents in the anticancer chemotherapy of some malignancies, are though often associated with severe systemic toxicity (i.e., neurotoxicity), especially after long-term treatments. The objective of the current developments is to produce novel nanoformulations with improved lipophilicity and passive diffusion, promoting intracellular accumulation, while reducing toxicity and optimizing the concomitant treatment of chemo-/radiotherapy. Moreover, the blood brain barrier (BBB) prevents the access of the drugs to the brain and accumulation in tumour cells, so it represents a key challenge for GB management. The development of novel nanomedicines with the ability to (i) encapsulate Pt-based drugs and pro-drugs, (ii) cross the BBB, and (iii) specifically target cancer cells represents a promising approach to increase the therapeutic effect of the anticancer drugs and reduce undesired side effects. In this review, a critical discussion is presented concerning different families of nanoparticles able to encapsulate platinum anticancer drugs and their application for GB treatment, emphasizing their potential for increasing the effectiveness of platinum-based drugs. Keywords: glioblastoma; platinum drugs; nanoformulation; chemotherapy; brain tumours Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Fri May 12 08:07:28 CEST 2023 ModDate: Fri May 12 08:09:38 CEST 2023 ID: 0xf0d64a56ee17bd9907a1ab9b7360ce72, 0xf0d64a56ee17bd9907a1ab9b7360ce72 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: BZPZJK+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: BZPZJK+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: DTVAIO+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: DTVAIO+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ENLEMO+VnURWPalladioL-Bold FontSubset: true FirstChar: 243 LastChar: 243 FontDescriptor: FontName: ENLEMO+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: NOVUER+EURM10 FontSubset: true FirstChar: 11 LastChar: 34 FontDescriptor: FontName: NOVUER+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: JEAHRS+URWPalladioL-Ital FontSubset: true FirstChar: 3 LastChar: 151 FontDescriptor: FontName: JEAHRS+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: TAQQTO+CMSY10 FontSubset: true FirstChar: 6 LastChar: 14 FontDescriptor: FontName: TAQQTO+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: MWHIBA+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: MWHIBA+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 125, 281, 152, 290 Annotation: Subtype: Link Rect: 34, 269, 133, 278 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 126, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 147, 87 Annotation: Subtype: Link Rect: 34, 756, 171, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 234, 660, 245, 674 Annotation: Subtype: Link Rect: 359, 660, 370, 674 Annotation: Subtype: Link Rect: 148, 650, 159, 661 Annotation: Subtype: Link Rect: 136, 17, 278, 28 Annotation: Subtype: Link Rect: 386, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 366, 87, 385 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 209, 736, 216, 744 ActionDest: 326 Annotation: Subtype: Link Rect: 287, 710, 294, 719 ActionDest: 326 Annotation: Subtype: Link Rect: 549, 698, 556, 707 ActionDest: 326 Annotation: Subtype: Link Rect: 294, 648, 301, 657 ActionDest: 326 Annotation: Subtype: Link Rect: 302, 647, 308, 657 ActionDest: 326 Annotation: Subtype: Link Rect: 549, 622, 556, 631 ActionDest: 326 Annotation: Subtype: Link Rect: 497, 585, 504, 594 ActionDest: 326 Annotation: Subtype: Link Rect: 549, 547, 556, 556 ActionDest: 326 Annotation: Subtype: Link Rect: 549, 522, 556, 531 ActionDest: 326 Annotation: Subtype: Link Rect: 211, 384, 223, 393 ActionDest: 326 Annotation: Subtype: Link Rect: 402, 372, 414, 380 ActionDest: 326 Annotation: Subtype: Link Rect: 226, 321, 233, 330 ActionDest: 326 Annotation: Subtype: Link Rect: 497, 208, 509, 217 ActionDest: 326 Annotation: Subtype: Link Rect: 289, 158, 301, 167 ActionDest: 326 Annotation: Subtype: Link Rect: 304, 158, 316, 167 ActionDest: 326 Annotation: Subtype: Link Rect: 350, 145, 362, 154 ActionDest: 326 Annotation: Subtype: Link Rect: 256, 120, 268, 129 ActionDest: 326 Annotation: Subtype: Link Rect: 372, 70, 384, 79 ActionDest: 326 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 478, 723, 490, 732 ActionDest: 326 Annotation: Subtype: Link Rect: 362, 698, 374, 707 ActionDest: 326 Annotation: Subtype: Link Rect: 218, 673, 230, 682 ActionDest: 326 Annotation: Subtype: Link Rect: 390, 673, 402, 682 ActionDest: 326 Annotation: Subtype: Link Rect: 193, 647, 205, 657 ActionDest: 326 Annotation: Subtype: Link Rect: 277, 585, 289, 594 ActionDest: 326 Annotation: Subtype: Link Rect: 451, 535, 463, 544 ActionDest: 326 Annotation: Subtype: Link Rect: 313, 509, 325, 519 ActionDest: 329 Annotation: Subtype: Link Rect: 249, 422, 261, 431 ActionDest: 329 Annotation: Subtype: Link Rect: 212, 396, 224, 406 ActionDest: 329 Annotation: Subtype: Link Rect: 415, 371, 427, 380 ActionDest: 329 Annotation: Subtype: Link Rect: 449, 283, 461, 293 ActionDest: 329 Annotation: Subtype: Link Rect: 215, 145, 227, 154 ActionDest: 329 Annotation: Subtype: Link Rect: 508, 145, 520, 154 ActionDest: 329 Annotation: Subtype: Link Rect: 460, 95, 472, 104 ActionDest: 329 Annotation: Subtype: Link Rect: 345, 70, 356, 79 ActionDest: 329 Annotation: Subtype: Link Rect: 357, 70, 369, 79 ActionDest: 329 Annotation: Subtype: Link Rect: 372, 70, 384, 79 ActionDest: 329 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 553, 733, 560, 745 ActionDest: 71 Annotation: Subtype: Link Rect: 419, 723, 431, 732 ActionDest: 329 Annotation: Subtype: Link Rect: 546, 460, 557, 468 ActionDest: 329 Annotation: Subtype: Link Rect: 529, 425, 541, 434 ActionDest: 329 Annotation: Subtype: Link Rect: 544, 425, 556, 434 ActionDest: 329 Annotation: Subtype: Link Rect: 397, 412, 409, 421 ActionDest: 329 Annotation: Subtype: Link Rect: 319, 400, 331, 409 ActionDest: 329 Annotation: Subtype: Link Rect: 331, 400, 343, 409 ActionDest: 329 Annotation: Subtype: Link Rect: 344, 400, 356, 409 ActionDest: 329 Annotation: Subtype: Link Rect: 243, 387, 255, 396 ActionDest: 329 Annotation: Subtype: Link Rect: 225, 374, 237, 384 ActionDest: 329 Annotation: Subtype: Link Rect: 240, 337, 252, 346 ActionDest: 329 Annotation: Subtype: Link Rect: 375, 262, 387, 271 ActionDest: 329 Annotation: Subtype: Link Rect: 493, 249, 505, 258 ActionDest: 329 Annotation: Subtype: Link Rect: 328, 236, 340, 245 ActionDest: 329 Annotation: Subtype: Link Rect: 411, 236, 423, 245 ActionDest: 329 Annotation: Subtype: Link Rect: 424, 236, 436, 245 ActionDest: 332 Annotation: Subtype: Link Rect: 237, 224, 249, 233 ActionDest: 332 Annotation: Subtype: Link Rect: 359, 224, 371, 233 ActionDest: 332 Annotation: Subtype: Link Rect: 371, 224, 383, 233 ActionDest: 332 Annotation: Subtype: Link Rect: 470, 224, 482, 233 ActionDest: 332 Annotation: Subtype: Link Rect: 224, 211, 236, 220 ActionDest: 332 Annotation: Subtype: Link Rect: 422, 211, 434, 220 ActionDest: 332 Annotation: Subtype: Link Rect: 519, 211, 531, 220 ActionDest: 332 Annotation: Subtype: Link Rect: 213, 199, 225, 208 ActionDest: 332 Annotation: Subtype: Link Rect: 530, 199, 542, 208 ActionDest: 332 Annotation: Subtype: Link Rect: 469, 174, 481, 183 ActionDest: 332 Annotation: Subtype: Link Rect: 513, 123, 525, 132 ActionDest: 332 Annotation: Subtype: Link Rect: 313, 86, 325, 95 ActionDest: 329 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 193, 698, 205, 707 ActionDest: 332 Annotation: Subtype: Link Rect: 206, 698, 217, 707 ActionDest: 332 Annotation: Subtype: Link Rect: 346, 698, 358, 707 ActionDest: 332 Annotation: Subtype: Link Rect: 448, 698, 460, 707 ActionDest: 332 Annotation: Subtype: Link Rect: 544, 673, 556, 682 ActionDest: 332 Annotation: Subtype: Link Rect: 202, 647, 213, 657 ActionDest: 332 Annotation: Subtype: Link Rect: 375, 597, 387, 606 ActionDest: 332 Annotation: Subtype: Link Rect: 226, 585, 238, 594 ActionDest: 332 Annotation: Subtype: Link Rect: 238, 585, 250, 594 ActionDest: 332 Annotation: Subtype: Link Rect: 436, 585, 447, 594 ActionDest: 332 Annotation: Subtype: Link Rect: 497, 585, 509, 594 ActionDest: 332 Annotation: Subtype: Link Rect: 195, 547, 207, 556 ActionDest: 335 Annotation: Subtype: Link Rect: 194, 472, 206, 481 ActionDest: 335 Annotation: Subtype: Link Rect: 512, 447, 524, 456 ActionDest: 335 Annotation: Subtype: Link Rect: 524, 447, 536, 456 ActionDest: 335 Annotation: Subtype: Link Rect: 388, 434, 400, 443 ActionDest: 335 Annotation: Subtype: Link Rect: 401, 434, 413, 443 ActionDest: 335 Annotation: Subtype: Link Rect: 525, 422, 537, 431 ActionDest: 335 Annotation: Subtype: Link Rect: 261, 371, 273, 380 ActionDest: 329 Annotation: Subtype: Link Rect: 456, 359, 468, 368 ActionDest: 335 Annotation: Subtype: Link Rect: 468, 359, 480, 368 ActionDest: 335 Annotation: Subtype: Link Rect: 224, 321, 236, 330 ActionDest: 335 Annotation: Subtype: Link Rect: 467, 283, 479, 293 ActionDest: 335 Annotation: Subtype: Link Rect: 482, 283, 494, 293 ActionDest: 335 Annotation: Subtype: Link Rect: 544, 258, 556, 267 ActionDest: 335 Annotation: Subtype: Link Rect: 492, 233, 504, 242 ActionDest: 335 Annotation: Subtype: Link Rect: 330, 196, 342, 205 ActionDest: 335 Annotation: Subtype: Link Rect: 343, 196, 355, 205 ActionDest: 335 Annotation: Subtype: Link Rect: 232, 183, 244, 192 ActionDest: 335 Annotation: Subtype: Link Rect: 307, 183, 319, 192 ActionDest: 332 Annotation: Subtype: Link Rect: 320, 183, 332, 192 ActionDest: 335 Annotation: Subtype: Link Rect: 385, 183, 397, 192 ActionDest: 335 Annotation: Subtype: Link Rect: 455, 183, 467, 192 ActionDest: 335 Annotation: Subtype: Link Rect: 532, 183, 544, 192 ActionDest: 335 Annotation: Subtype: Link Rect: 545, 183, 556, 192 ActionDest: 335 Annotation: Subtype: Link Rect: 222, 170, 234, 180 ActionDest: 338 Annotation: Subtype: Link Rect: 197, 145, 209, 154 ActionDest: 338 Annotation: Subtype: Link Rect: 514, 145, 526, 154 ActionDest: 338 Annotation: Subtype: Link Rect: 277, 120, 289, 129 ActionDest: 338 Annotation: Subtype: Link Rect: 539, 108, 556, 117 ActionDest: 338 Annotation: Subtype: Link Rect: 421, 70, 438, 79 ActionDest: 338 Annotation: Subtype: Link Rect: 438, 70, 455, 79 ActionDest: 338 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 302, 735, 319, 744 ActionDest: 338 Annotation: Subtype: Link Rect: 544, 647, 556, 656 ActionDest: 329 Annotation: Subtype: Link Rect: 544, 534, 556, 543 ActionDest: 329 Annotation: Subtype: Link Rect: 363, 509, 380, 518 ActionDest: 338 Annotation: Subtype: Link Rect: 427, 471, 444, 480 ActionDest: 338 Annotation: Subtype: Link Rect: 389, 446, 406, 455 ActionDest: 338 Annotation: Subtype: Link Rect: 426, 396, 442, 405 ActionDest: 338 Annotation: Subtype: Link Rect: 443, 396, 460, 405 ActionDest: 338 Annotation: Subtype: Link Rect: 477, 345, 494, 354 ActionDest: 338 Annotation: Subtype: Link Rect: 372, 257, 389, 266 ActionDest: 338 Annotation: Subtype: Link Rect: 409, 245, 425, 254 ActionDest: 338 Annotation: Subtype: Link Rect: 524, 194, 541, 203 ActionDest: 338 Annotation: Subtype: Link Rect: 519, 144, 536, 153 ActionDest: 338 Annotation: Subtype: Link Rect: 539, 144, 556, 153 ActionDest: 338 Annotation: Subtype: Link Rect: 448, 119, 465, 128 ActionDest: 338 Annotation: Subtype: Link Rect: 302, 94, 319, 103 ActionDest: 338 Annotation: Subtype: Link Rect: 319, 94, 336, 103 ActionDest: 338 Annotation: Subtype: Link Rect: 428, 81, 445, 90 ActionDest: 338 Annotation: Subtype: Link Rect: 481, 69, 498, 78 ActionDest: 338 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 319, 735, 335, 744 ActionDest: 341 Annotation: Subtype: Link Rect: 539, 698, 556, 707 ActionDest: 341 Annotation: Subtype: Link Rect: 389, 648, 406, 657 ActionDest: 341 Annotation: Subtype: Link Rect: 459, 622, 476, 631 ActionDest: 341 Annotation: Subtype: Link Rect: 495, 522, 507, 531 ActionDest: 329 Annotation: Subtype: Link Rect: 215, 406, 222, 418 ActionDest: 110 Annotation: Subtype: Link Rect: 229, 409, 246, 418 ActionDest: 341 Annotation: Subtype: Link Rect: 338, 73, 353, 81 ActionDest: 341 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 231, 710, 248, 719 ActionDest: 341 Annotation: Subtype: Link Rect: 215, 685, 232, 694 ActionDest: 341 Annotation: Subtype: Link Rect: 462, 582, 469, 594 ActionDest: 286 Annotation: Subtype: Link Rect: 240, 534, 256, 543 ActionDest: 341 Annotation: Subtype: Link Rect: 457, 521, 474, 530 ActionDest: 341 Annotation: Subtype: Link Rect: 476, 521, 493, 530 ActionDest: 341 Annotation: Subtype: Link Rect: 194, 509, 210, 518 ActionDest: 341 Annotation: Subtype: Link Rect: 213, 509, 230, 518 ActionDest: 341 Annotation: Subtype: Link Rect: 333, 509, 350, 518 ActionDest: 341 Annotation: Subtype: Link Rect: 350, 509, 367, 518 ActionDest: 341 Annotation: Subtype: Link Rect: 428, 509, 445, 518 ActionDest: 341 Annotation: Subtype: Link Rect: 446, 509, 462, 518 ActionDest: 341 Annotation: Subtype: Link Rect: 519, 509, 536, 518 ActionDest: 341 Annotation: Subtype: Link Rect: 539, 509, 556, 518 ActionDest: 341 Annotation: Subtype: Link Rect: 233, 496, 250, 505 ActionDest: 341 Annotation: Subtype: Link Rect: 251, 496, 268, 505 ActionDest: 341 Annotation: Subtype: Link Rect: 489, 496, 506, 505 ActionDest: 341 Annotation: Subtype: Link Rect: 509, 496, 526, 505 ActionDest: 344 Annotation: Subtype: Link Rect: 232, 484, 249, 493 ActionDest: 344 Annotation: Subtype: Link Rect: 252, 484, 269, 493 ActionDest: 344 Annotation: Subtype: Link Rect: 268, 471, 280, 480 ActionDest: 338 Annotation: Subtype: Link Rect: 280, 471, 297, 480 ActionDest: 344 Annotation: Subtype: Link Rect: 300, 471, 317, 480 ActionDest: 344 Annotation: Subtype: Link Rect: 317, 321, 334, 330 ActionDest: 344 Annotation: Subtype: Link Rect: 363, 233, 380, 242 ActionDest: 344 Annotation: Subtype: Link Rect: 471, 220, 488, 229 ActionDest: 344 Annotation: Subtype: Link Rect: 295, 180, 302, 192 ActionDest: 142 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 341, 452, 356, 460 ActionDest: 344 Annotation: Subtype: Link Rect: 211, 404, 228, 413 ActionDest: 344 Annotation: Subtype: Link Rect: 441, 404, 458, 413 ActionDest: 344 Annotation: Subtype: Link Rect: 297, 392, 314, 401 ActionDest: 344 Annotation: Subtype: Link Rect: 363, 304, 380, 313 ActionDest: 344 Annotation: Subtype: Link Rect: 191, 266, 208, 275 ActionDest: 344 Annotation: Subtype: Link Rect: 354, 216, 371, 225 ActionDest: 344 Annotation: Subtype: Link Rect: 430, 153, 447, 162 ActionDest: 344 Annotation: Subtype: Link Rect: 401, 90, 418, 100 ActionDest: 347 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 241, 710, 258, 719 ActionDest: 347 Annotation: Subtype: Link Rect: 539, 685, 556, 694 ActionDest: 347 Annotation: Subtype: Link Rect: 485, 648, 502, 657 ActionDest: 347 Annotation: Subtype: Link Rect: 408, 622, 425, 631 ActionDest: 347 Annotation: Subtype: Link Rect: 197, 510, 214, 519 ActionDest: 347 Annotation: Subtype: Link Rect: 517, 434, 534, 443 ActionDest: 347 Annotation: Subtype: Link Rect: 427, 359, 444, 368 ActionDest: 347 Annotation: Subtype: Link Rect: 495, 296, 511, 305 ActionDest: 347 Annotation: Subtype: Link Rect: 240, 145, 257, 154 ActionDest: 347 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 229, 610, 246, 619 ActionDest: 347 Annotation: Subtype: Link Rect: 262, 497, 279, 506 ActionDest: 344 Annotation: Subtype: Link Rect: 436, 384, 453, 393 ActionDest: 347 Annotation: Subtype: Link Rect: 539, 371, 556, 380 ActionDest: 347 Annotation: Subtype: Link Rect: 434, 321, 451, 330 ActionDest: 347 Annotation: Subtype: Link Rect: 500, 258, 517, 267 ActionDest: 347 Annotation: Subtype: Link Rect: 518, 258, 535, 267 ActionDest: 347 Annotation: Subtype: Link Rect: 450, 233, 467, 242 ActionDest: 347 Annotation: Subtype: Link Rect: 332, 195, 349, 204 ActionDest: 347 Annotation: Subtype: Link Rect: 290, 142, 297, 154 ActionDest: 178 Annotation: Subtype: Link Rect: 304, 145, 321, 154 ActionDest: 347 Annotation: Subtype: Link Rect: 470, 95, 487, 104 ActionDest: 347 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 292, 374, 308, 383 ActionDest: 347 Annotation: Subtype: Link Rect: 201, 289, 218, 298 ActionDest: 347 Annotation: Subtype: Link Rect: 201, 114, 213, 123 ActionDest: 338 Annotation: Subtype: Link Rect: 493, 88, 510, 98 ActionDest: 347 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 376, 597, 393, 606 ActionDest: 338 Annotation: Subtype: Link Rect: 206, 572, 223, 581 ActionDest: 350 Annotation: Subtype: Link Rect: 196, 532, 203, 544 ActionDest: 215 Annotation: Subtype: Link Rect: 211, 534, 228, 543 ActionDest: 350 Annotation: Subtype: Link Rect: 207, 80, 222, 88 ActionDest: 350 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 511, 698, 528, 707 ActionDest: 350 Annotation: Subtype: Link Rect: 522, 635, 539, 644 ActionDest: 350 Annotation: Subtype: Link Rect: 314, 535, 331, 544 ActionDest: 350 Annotation: Subtype: Link Rect: 539, 471, 556, 481 ActionDest: 350 Annotation: Subtype: Link Rect: 376, 409, 388, 418 ActionDest: 335 Annotation: Subtype: Link Rect: 381, 381, 388, 393 ActionDest: 250 Annotation: Subtype: Link Rect: 199, 371, 216, 380 ActionDest: 341 Annotation: Subtype: Link Rect: 466, 208, 483, 217 ActionDest: 350 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 246, 723, 263, 732 ActionDest: 350 Annotation: Subtype: Link Rect: 446, 355, 461, 363 ActionDest: 341 Annotation: Subtype: Link Rect: 294, 295, 311, 304 ActionDest: 344 Annotation: Subtype: Link Rect: 349, 269, 366, 279 ActionDest: 350 Annotation: Subtype: Link Rect: 257, 179, 264, 191 ActionDest: 286 Annotation: Subtype: Link Rect: 271, 182, 283, 191 ActionDest: 338 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 450, 320, 461, 329 ActionDest: 338 Annotation: Subtype: Link Rect: 533, 182, 549, 191 ActionDest: 344 Annotation: Subtype: Link Rect: 533, 117, 549, 125 ActionDest: 344 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 533, 637, 549, 646 ActionDest: 344 Annotation: Subtype: Link Rect: 533, 567, 549, 575 ActionDest: 344 Annotation: Subtype: Link Rect: 533, 485, 549, 494 ActionDest: 344 Annotation: Subtype: Link Rect: 533, 409, 549, 418 ActionDest: 344 Annotation: Subtype: Link Rect: 533, 355, 549, 363 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 301, 549, 309 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 252, 549, 261 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 204, 549, 212 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 133, 549, 141 ActionDest: 347 Page: Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 533, 637, 549, 646 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 572, 549, 581 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 485, 544, 494 ActionDest: 335 Annotation: Subtype: Link Rect: 533, 393, 549, 401 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 322, 549, 331 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 263, 549, 271 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 203, 549, 211 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 127, 549, 135 ActionDest: 347 Page: Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 533, 626, 549, 635 ActionDest: 347 Annotation: Subtype: Link Rect: 533, 556, 549, 564 ActionDest: 350 Annotation: Subtype: Link Rect: 533, 507, 549, 516 ActionDest: 350 Annotation: Subtype: Link Rect: 533, 442, 549, 450 ActionDest: 350 Annotation: Subtype: Link Rect: 533, 366, 549, 374 ActionDest: 341 Annotation: Subtype: Link Rect: 533, 284, 544, 293 ActionDest: 335 Annotation: Subtype: Link Rect: 533, 181, 549, 189 ActionDest: 350 Annotation: Subtype: Link Rect: 533, 105, 549, 113 ActionDest: 350 Page: Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 533, 621, 549, 629 ActionDest: 350 Annotation: Subtype: Link Rect: 533, 545, 549, 553 ActionDest: 350 Annotation: Subtype: Link Rect: 533, 480, 549, 488 ActionDest: 350 Annotation: Subtype: Link Rect: 258, 364, 275, 373 ActionDest: 350 Annotation: Subtype: Link Rect: 250, 327, 267, 336 ActionDest: 350 Annotation: Subtype: Link Rect: 360, 276, 377, 286 ActionDest: 338 Annotation: Subtype: Link Rect: 230, 226, 241, 235 ActionDest: 338 Annotation: Subtype: Link Rect: 496, 201, 513, 210 ActionDest: 350 Annotation: Subtype: Link Rect: 520, 176, 537, 185 ActionDest: 350 Page: Sequence: 21 Annotations: Annotation: Subtype: Link Rect: 290, 660, 307, 669 ActionDest: 350 Annotation: Subtype: Link Rect: 370, 660, 387, 669 ActionDest: 350 Annotation: Subtype: Link Rect: 460, 660, 477, 669 ActionDest: 350 Annotation: Subtype: Link Rect: 478, 660, 495, 669 ActionDest: 350 Annotation: Subtype: Link Rect: 459, 522, 476, 531 ActionDest: 350 Annotation: Subtype: Link Rect: 353, 497, 365, 506 ActionDest: 329 Annotation: Subtype: Link Rect: 413, 484, 425, 493 ActionDest: 329 Annotation: Subtype: Link Rect: 425, 484, 437, 493 ActionDest: 329 Annotation: Subtype: Link Rect: 488, 459, 505, 468 ActionDest: 350 Annotation: Subtype: Link Rect: 315, 434, 332, 443 ActionDest: 350 Annotation: Subtype: Link Rect: 333, 434, 350, 443 ActionDest: 350 Annotation: Subtype: Link Rect: 394, 422, 411, 431 ActionDest: 354 Annotation: Subtype: Link Rect: 451, 396, 468, 406 ActionDest: 354 Annotation: Subtype: Link Rect: 395, 384, 411, 393 ActionDest: 350 Annotation: Subtype: Link Rect: 263, 246, 280, 255 ActionDest: 354 Annotation: Subtype: Link Rect: 384, 120, 396, 129 ActionDest: 329 Annotation: Subtype: Link Rect: 396, 120, 413, 129 ActionDest: 347 Annotation: Subtype: Link Rect: 267, 107, 284, 117 ActionDest: 354 Page: Sequence: 22 Annotations: Annotation: Subtype: Link Rect: 190, 447, 207, 456 ActionDest: 354 Annotation: Subtype: Link Rect: 207, 447, 224, 456 ActionDest: 354 Annotation: Subtype: Link Rect: 339, 98, 454, 109 Page: Sequence: 23 Annotations: Annotation: Subtype: Link Rect: 344, 592, 381, 602 Annotation: Subtype: Link Rect: 509, 568, 547, 579 Annotation: Subtype: Link Rect: 349, 545, 387, 556 Annotation: Subtype: Link Rect: 104, 523, 141, 533 Annotation: Subtype: Link Rect: 481, 511, 519, 522 Annotation: Subtype: Link Rect: 225, 488, 263, 499 Annotation: Subtype: Link Rect: 59, 454, 96, 464 Annotation: Subtype: Link Rect: 151, 431, 189, 441 Annotation: Subtype: Link Rect: 328, 407, 366, 418 Annotation: Subtype: Link Rect: 287, 384, 325, 395 Annotation: Subtype: Link Rect: 419, 349, 457, 360 Annotation: Subtype: Link Rect: 517, 326, 554, 337 Annotation: Subtype: Link Rect: 444, 303, 482, 314 Annotation: Subtype: Link Rect: 197, 281, 235, 291 Annotation: Subtype: Link Rect: 59, 258, 96, 268 Annotation: Subtype: Link Rect: 403, 234, 441, 245 Annotation: Subtype: Link Rect: 371, 224, 408, 234 Annotation: Subtype: Link Rect: 246, 200, 283, 211 Annotation: Subtype: Link Rect: 231, 177, 269, 188 Annotation: Subtype: Link Rect: 369, 154, 406, 165 Annotation: Subtype: Link Rect: 127, 120, 164, 130 Annotation: Subtype: Link Rect: 86, 97, 124, 107 Annotation: Subtype: Link Rect: 100, 63, 137, 73 Page: Sequence: 24 Annotations: Annotation: Subtype: Link Rect: 245, 722, 282, 733 Annotation: Subtype: Link Rect: 165, 699, 203, 710 Annotation: Subtype: Link Rect: 190, 664, 227, 675 Annotation: Subtype: Link Rect: 215, 642, 253, 652 Annotation: Subtype: Link Rect: 150, 619, 188, 629 Annotation: Subtype: Link Rect: 464, 606, 501, 617 Annotation: Subtype: Link Rect: 507, 606, 544, 617 Annotation: Subtype: Link Rect: 281, 584, 318, 594 Annotation: Subtype: Link Rect: 325, 584, 361, 594 Annotation: Subtype: Link Rect: 178, 561, 215, 571 Annotation: Subtype: Link Rect: 519, 537, 557, 548 Annotation: Subtype: Link Rect: 59, 527, 95, 537 Annotation: Subtype: Link Rect: 439, 503, 477, 514 Annotation: Subtype: Link Rect: 483, 503, 519, 514 Annotation: Subtype: Link Rect: 131, 469, 168, 479 Annotation: Subtype: Link Rect: 312, 445, 350, 456 Annotation: Subtype: Link Rect: 356, 445, 392, 456 Annotation: Subtype: Link Rect: 126, 400, 164, 410 Annotation: Subtype: Link Rect: 276, 365, 313, 376 Annotation: Subtype: Link Rect: 364, 330, 402, 341 Annotation: Subtype: Link Rect: 408, 330, 444, 341 Annotation: Subtype: Link Rect: 59, 297, 95, 307 Annotation: Subtype: Link Rect: 232, 273, 269, 284 Annotation: Subtype: Link Rect: 276, 273, 312, 284 Annotation: Subtype: Link Rect: 251, 238, 289, 249 Annotation: Subtype: Link Rect: 450, 204, 487, 215 Annotation: Subtype: Link Rect: 104, 182, 141, 192 Annotation: Subtype: Link Rect: 482, 158, 519, 169 Annotation: Subtype: Link Rect: 400, 135, 437, 146 Annotation: Subtype: Link Rect: 191, 77, 229, 88 Page: Sequence: 25 Annotations: Annotation: Subtype: Link Rect: 408, 699, 444, 710 Annotation: Subtype: Link Rect: 238, 664, 276, 675 Annotation: Subtype: Link Rect: 282, 664, 318, 675 Annotation: Subtype: Link Rect: 232, 641, 270, 652 Annotation: Subtype: Link Rect: 276, 641, 312, 652 Annotation: Subtype: Link Rect: 410, 618, 447, 629 Annotation: Subtype: Link Rect: 454, 618, 490, 629 Annotation: Subtype: Link Rect: 117, 584, 155, 594 Annotation: Subtype: Link Rect: 161, 584, 197, 594 Annotation: Subtype: Link Rect: 131, 550, 168, 560 Annotation: Subtype: Link Rect: 59, 515, 96, 525 Annotation: Subtype: Link Rect: 178, 480, 216, 491 Annotation: Subtype: Link Rect: 171, 446, 208, 456 Annotation: Subtype: Link Rect: 196, 411, 233, 422 Annotation: Subtype: Link Rect: 519, 388, 557, 399 Annotation: Subtype: Link Rect: 59, 377, 95, 387 Annotation: Subtype: Link Rect: 372, 353, 409, 364 Annotation: Subtype: Link Rect: 416, 353, 452, 364 Annotation: Subtype: Link Rect: 194, 331, 232, 341 Annotation: Subtype: Link Rect: 238, 331, 274, 341 Annotation: Subtype: Link Rect: 104, 308, 141, 318 Annotation: Subtype: Link Rect: 337, 284, 374, 295 Annotation: Subtype: Link Rect: 509, 227, 547, 238 Annotation: Subtype: Link Rect: 437, 204, 474, 215 Annotation: Subtype: Link Rect: 117, 182, 155, 192 Annotation: Subtype: Link Rect: 59, 147, 96, 157 Annotation: Subtype: Link Rect: 468, 123, 506, 134 Annotation: Subtype: Link Rect: 512, 123, 548, 134 Annotation: Subtype: Link Rect: 178, 78, 215, 88 Annotation: Subtype: Link Rect: 222, 78, 258, 88 Page: Sequence: 26 Annotations: Annotation: Subtype: Link Rect: 261, 722, 298, 733 Annotation: Subtype: Link Rect: 304, 722, 340, 733 Annotation: Subtype: Link Rect: 519, 699, 557, 710 Annotation: Subtype: Link Rect: 59, 688, 95, 698 Annotation: Subtype: Link Rect: 475, 664, 512, 675 Annotation: Subtype: Link Rect: 321, 629, 358, 640 Annotation: Subtype: Link Rect: 189, 596, 227, 606 Annotation: Subtype: Link Rect: 516, 572, 554, 583 Annotation: Subtype: Link Rect: 269, 526, 307, 537 Annotation: Subtype: Link Rect: 453, 503, 491, 514 Annotation: Subtype: Link Rect: 497, 503, 533, 514 Annotation: Subtype: Link Rect: 59, 469, 96, 479 Annotation: Subtype: Link Rect: 102, 469, 138, 479 Annotation: Subtype: Link Rect: 460, 445, 497, 456 Annotation: Subtype: Link Rect: 504, 445, 540, 456 Annotation: Subtype: Link Rect: 413, 422, 450, 433 Annotation: Subtype: Link Rect: 420, 399, 457, 410 Annotation: Subtype: Link Rect: 126, 366, 164, 376 Annotation: Subtype: Link Rect: 59, 331, 96, 341 Annotation: Subtype: Link Rect: 504, 319, 541, 330 Annotation: Subtype: Link Rect: 59, 297, 96, 307 Annotation: Subtype: Link Rect: 150, 262, 188, 272 Annotation: Subtype: Link Rect: 226, 227, 264, 238 Annotation: Subtype: Link Rect: 270, 227, 306, 238 Annotation: Subtype: Link Rect: 59, 193, 96, 203 Annotation: Subtype: Link Rect: 172, 159, 209, 169 Annotation: Subtype: Link Rect: 215, 159, 251, 169 Annotation: Subtype: Link Rect: 59, 124, 96, 134 Annotation: Subtype: Link Rect: 519, 100, 557, 111 Annotation: Subtype: Link Rect: 59, 90, 95, 100 Page: Sequence: 27 Annotations: Annotation: Subtype: Link Rect: 59, 711, 96, 721 Annotation: Subtype: Link Rect: 102, 711, 138, 721 Annotation: Subtype: Link Rect: 238, 676, 275, 687 Annotation: Subtype: Link Rect: 386, 652, 424, 664 Annotation: Subtype: Link Rect: 506, 629, 544, 640 Annotation: Subtype: Link Rect: 510, 606, 548, 617 Annotation: Subtype: Link Rect: 519, 583, 557, 594 Annotation: Subtype: Link Rect: 59, 573, 95, 583 Annotation: Subtype: Link Rect: 104, 550, 141, 560 Annotation: Subtype: Link Rect: 147, 550, 183, 560 Annotation: Subtype: Link Rect: 95, 515, 133, 525 Annotation: Subtype: Link Rect: 139, 515, 175, 525 Annotation: Subtype: Link Rect: 113, 481, 150, 491 Annotation: Subtype: Link Rect: 520, 457, 557, 468 Annotation: Subtype: Link Rect: 170, 423, 208, 433 Annotation: Subtype: Link Rect: 494, 399, 531, 410 Annotation: Subtype: Link Rect: 493, 365, 530, 376 Annotation: Subtype: Link Rect: 380, 342, 418, 353 Annotation: Subtype: Link Rect: 59, 308, 96, 318 Annotation: Subtype: Link Rect: 453, 284, 491, 295 Annotation: Subtype: Link Rect: 438, 261, 475, 272 Annotation: Subtype: Link Rect: 59, 239, 96, 249 Annotation: Subtype: Link Rect: 102, 239, 138, 249 Annotation: Subtype: Link Rect: 462, 215, 500, 226 Annotation: Subtype: Link Rect: 470, 204, 508, 215 Annotation: Subtype: Link Rect: 514, 204, 550, 215 Annotation: Subtype: Link Rect: 86, 170, 124, 180 Annotation: Subtype: Link Rect: 130, 170, 166, 180 Annotation: Subtype: Link Rect: 269, 136, 306, 146 Annotation: Subtype: Link Rect: 424, 100, 462, 111 Annotation: Subtype: Link Rect: 468, 77, 506, 88 Page: Sequence: 28 Annotations: Annotation: Subtype: Link Rect: 59, 711, 96, 721 Annotation: Subtype: Link Rect: 113, 676, 150, 687 Annotation: Subtype: Link Rect: 156, 676, 192, 687 Annotation: Subtype: Link Rect: 371, 652, 409, 664 Annotation: Subtype: Link Rect: 415, 652, 451, 664 Annotation: Subtype: Link Rect: 118, 630, 155, 640 Annotation: Subtype: Link Rect: 161, 630, 197, 640 Annotation: Subtype: Link Rect: 113, 607, 150, 617 Annotation: Subtype: Link Rect: 188, 538, 226, 548 Annotation: Subtype: Link Rect: 411, 514, 449, 525 Annotation: Subtype: Link Rect: 470, 491, 507, 502 Annotation: Subtype: Link Rect: 448, 468, 485, 479 Annotation: Subtype: Link Rect: 449, 445, 486, 456 Annotation: Subtype: Link Rect: 492, 445, 528, 456 Annotation: Subtype: Link Rect: 140, 412, 177, 422 Annotation: Subtype: Link Rect: 184, 412, 220, 422 Annotation: Subtype: Link Rect: 95, 377, 133, 387 Annotation: Subtype: Link Rect: 139, 377, 175, 387 Annotation: Subtype: Link Rect: 334, 342, 372, 353 Annotation: Subtype: Link Rect: 347, 319, 385, 330 Annotation: Subtype: Link Rect: 59, 285, 96, 295 Annotation: Subtype: Link Rect: 180, 251, 217, 261 Annotation: Subtype: Link Rect: 501, 204, 538, 215 Annotation: Subtype: Link Rect: 182, 170, 220, 180 Annotation: Subtype: Link Rect: 383, 146, 420, 157 Annotation: Subtype: Link Rect: 427, 146, 463, 157 Annotation: Subtype: Link Rect: 393, 123, 430, 134 Annotation: Subtype: Link Rect: 436, 123, 473, 134 Annotation: Subtype: Link Rect: 149, 101, 186, 111 Annotation: Subtype: Link Rect: 192, 101, 228, 111 Page: Sequence: 29 Annotations: Annotation: Subtype: Link Rect: 356, 722, 394, 733 Annotation: Subtype: Link Rect: 59, 688, 96, 698 Annotation: Subtype: Link Rect: 295, 664, 333, 675 Annotation: Subtype: Link Rect: 354, 641, 391, 652 Annotation: Subtype: Link Rect: 329, 618, 367, 629 Annotation: Subtype: Link Rect: 168, 596, 206, 606 Annotation: Subtype: Link Rect: 215, 573, 252, 583 Annotation: Subtype: Link Rect: 59, 538, 96, 548 Annotation: Subtype: Link Rect: 224, 514, 262, 525 Annotation: Subtype: Link Rect: 328, 491, 366, 502 Annotation: Subtype: Link Rect: 215, 469, 253, 479 Annotation: Subtype: Link Rect: 277, 446, 314, 456 Annotation: Subtype: Link Rect: 59, 412, 96, 422 Annotation: Subtype: Link Rect: 303, 389, 340, 399 Annotation: Subtype: Link Rect: 86, 354, 123, 364 Annotation: Subtype: Link Rect: 427, 319, 464, 330 Annotation: Subtype: Link Rect: 245, 296, 283, 307 Annotation: Subtype: Link Rect: 86, 262, 123, 272 Annotation: Subtype: Link Rect: 273, 227, 311, 238 Annotation: Subtype: Link Rect: 459, 192, 497, 203 Annotation: Subtype: Link Rect: 268, 158, 306, 169 Annotation: Subtype: Link Rect: 140, 101, 177, 111 Annotation: Subtype: Link Rect: 244, 77, 282, 88 Page: Sequence: 30 Annotations: Annotation: Subtype: Link Rect: 311, 710, 348, 721 Annotation: Subtype: Link Rect: 214, 688, 251, 698 Annotation: Subtype: Link Rect: 98, 653, 136, 664 Annotation: Subtype: Link Rect: 104, 619, 142, 629 Annotation: Subtype: Link Rect: 59, 584, 96, 594 Annotation: Subtype: Link Rect: 289, 550, 326, 560 Annotation: Subtype: Link Rect: 229, 514, 267, 525 Annotation: Subtype: Link Rect: 113, 481, 151, 491 Annotation: Subtype: Link Rect: 487, 457, 524, 468 Annotation: Subtype: Link Rect: 235, 423, 273, 433 Annotation: Subtype: Link Rect: 185, 389, 222, 399 Annotation: Subtype: Link Rect: 285, 365, 323, 376 Annotation: Subtype: Link Rect: 207, 331, 243, 341 Annotation: Subtype: Link Rect: 59, 297, 96, 307 Annotation: Subtype: Link Rect: 102, 297, 138, 307 Annotation: Subtype: Link Rect: 448, 273, 485, 284 Annotation: Subtype: Link Rect: 491, 273, 527, 284 Annotation: Subtype: Link Rect: 470, 250, 507, 261 Annotation: Subtype: Link Rect: 316, 215, 353, 226 Annotation: Subtype: Link Rect: 183, 181, 220, 192 Annotation: Subtype: Link Rect: 59, 147, 96, 157 Annotation: Subtype: Link Rect: 520, 123, 557, 134 Annotation: Subtype: Link Rect: 197, 89, 235, 100 Annotation: Subtype: Link Rect: 265, 66, 303, 77 Page: Sequence: 31 Annotations: Annotation: Subtype: Link Rect: 519, 722, 557, 733 Annotation: Subtype: Link Rect: 59, 711, 95, 721 Annotation: Subtype: Link Rect: 238, 676, 275, 687 Annotation: Subtype: Link Rect: 109, 642, 146, 652 Annotation: Subtype: Link Rect: 477, 618, 515, 629 Annotation: Subtype: Link Rect: 521, 618, 557, 629 Annotation: Subtype: Link Rect: 349, 583, 386, 594 Annotation: Subtype: Link Rect: 393, 583, 429, 594 Annotation: Subtype: Link Rect: 272, 561, 309, 571 Annotation: Subtype: Link Rect: 155, 526, 193, 537 Annotation: Subtype: Link Rect: 160, 492, 198, 502 Annotation: Subtype: Link Rect: 113, 458, 151, 468 Annotation: Subtype: Link Rect: 59, 423, 96, 433 Annotation: Subtype: Link Rect: 307, 399, 345, 410 Annotation: Subtype: Link Rect: 520, 376, 557, 387 Annotation: Subtype: Link Rect: 59, 366, 95, 376 Annotation: Subtype: Link Rect: 308, 342, 346, 353 Annotation: Subtype: Link Rect: 352, 342, 388, 353 Annotation: Subtype: Link Rect: 324, 307, 361, 318 Annotation: Subtype: Link Rect: 185, 274, 223, 284 Annotation: Subtype: Link Rect: 232, 227, 269, 238 Annotation: Subtype: Link Rect: 328, 193, 364, 203 Annotation: Subtype: Link Rect: 95, 159, 133, 169 Annotation: Subtype: Link Rect: 139, 159, 175, 169 Annotation: Subtype: Link Rect: 109, 136, 146, 146 Annotation: Subtype: Link Rect: 59, 113, 96, 123 Annotation: Subtype: Link Rect: 245, 89, 282, 100 Annotation: Subtype: Link Rect: 288, 89, 324, 100 Page: Sequence: 32 Annotations: Annotation: Subtype: Link Rect: 283, 710, 320, 721 Annotation: Subtype: Link Rect: 407, 687, 445, 698 Annotation: Subtype: Link Rect: 272, 665, 309, 675 Annotation: Subtype: Link Rect: 315, 665, 351, 675 Annotation: Subtype: Link Rect: 59, 630, 96, 640 Annotation: Subtype: Link Rect: 102, 630, 138, 640 Annotation: Subtype: Link Rect: 59, 596, 96, 606 Annotation: Subtype: Link Rect: 236, 560, 273, 571 Checksum: 2f0dbcf3 Type: CRC32 Checksum: 9a57f65a52fff8681e4a5a8897aadec9 Type: MD5 Checksum: 843c1baf320bbf903b69a7d57c8b1a0320dd1d3a Type: SHA-1