APPLICATION OF DIGITAL CELLULAR RADIO FOR MOBILE LOCATION ESTIMATION Khan et al. IIUM Engineering Journal, Vol. 20, No. 2, 2019 https://doi.org/10.31436/iiumej.v20i2.1136 RADIATION DOSE DELIVERED BY 125I, 103PD AND 131CS AND DOSE ENHANCEMENT BY GOLD NANOPARTICLE (GNP) SOLUTION IN PROSTATE BRACHYTHERAPY: A COMPARATIVE ANALYSIS BY MONTE CARLO SIMULATION HAMDA KHAN1, UMAIR AZIZ2*, ZAFAR ULLAH KORESHI2 1Department. of Mathematics, National University of Computer and Emerging Sciences, Islamabad, Pakistan. 2Department of Mechatronics Engineering, Air University, Islamabad, Pakistan. *Corresponding author: umair.aziz@mail.au.edu.pk (Received: 10th April 2019; Accepted: 1st August 2019; Published on-line:2nd December 2019) ABSTRACT: The energy deposition and radiation dose from commonly used radioisotopes, 125I,103Pd, and 131Cs, used for brachytherapy of cancers is estimated using Monte Carlo (MC) simulations. To enhance the dose, gold nanoparticle (GNP) solutions are injected into the tumor; this results in more effective and shorter therapy duration. It is thus important to estimate the dose enhancement factor (DEF) achievable by a radioisotope. The research presented in this paper thus focuses on a comparative analysis of radioisotopes. To estimate the radiation dose, the Monte Carlo N-particle code MCNP5 was used for a coupled photon-electron simulation of radiation transport from radiation emanating from seeds of radioisotopes implanted in the prostate at positions prescribed to deliver effective doses to the tumor while protecting neighbouring vital organs such as the rectum and urethra. The quantities tallied were the energy deposition (F6 tally) and the pulse heights (*F8 tally) in specified energy bins. The energy deposited in the tumor was used to estimate the absorbed dose to the prostate incorporating the transformations of the radioisotopes during decay. The absorbed dose was subsequently estimated for a GNP-tissue solution with a concentration of 25 mg Au/g of prostate tissue, modelled as a homogenous mixture. From the simulations, it was found that the lifetime absorbed dose is ~96 Gy from 98 seeds, each of 0.31 mCi, of 125I; ~102 Gy, from 115 seeds, each of 1.4 mCi, of 103Pd, and ~90 Gy from 131Cs seeds replacing 103Pd seeds of the same initial activity. The main advantage of 131Cs, over 125I and 103Pd, is observed in the larger dose rate (~26 cGy/hr) delivered initially i.e. in the first few days which is 1.5 and 5.7 times higher than that for 103Pd and 125I. The absorbed dose for 125I, 103Pd and 131Cs increases to ~245, ~130, ~187 Gy respectively with GNP-tissue solution of 25 mg Au/g tissue. From the analysis, it is found that while the lifetime absorbed dose of all three radioisotopes is of the same order, there are advantages in using 131Cs; these advantages are further quantified. ABSTRAK: Pemendapan tenaga dan dos sinaran radiasi daripada radioisotop yang biasa digunakan, 125I,103Pd, dan 131Cs, digunakan bagi terapibraki kanser dianggar menggunakan simulasi Monte Carlo (MC). Bagi meningkatkan dos, larutan partikel nano emas (GNP) telah disuntik ke dalam tumor; ini lebih memberi kesan dan mengurangkan masa terapi. Oleh itu, adalah penting menganggar faktor dos penggalak (DEF) dapat dicapai dengan radioisotop. Kajian ini mengfokuskan pada analisis perbandingan radioisotop. Bagi menganggarkan dos radiasi, kod Monte Carlo N-partikel MCNP5 telah digunakan pada simulasi pasangan foton-elektron pengangkutan radiasi daripada 176 Khan et al. IIUM Engineering Journal, Vol. 20, No. 2, 2019 https://doi.org/10.31436/iiumej.v20i2.1136 pancaran radioaktif benih radioisotop yang ditanam dalam prostat pada posisi yang disebut bagi mencetuskan dos penghantaran yang berkesan pada sel tumor. Dalam masa sama melindungi organ penting seperti rektum dan uretra. Kuantiti diselaras dengan pemendapan tenaga (selaras F6) dan ketinggian denyut (selaras *F8) dalam aras tenaga sebenar. Tenaga yang dienap dalam sel tumor ini telah digunakan bagi menganggarkan dos serapan pada prostat dengan menggabungkan transformasi radioisotop ketika susutan. Dos yang diserap telah kemudiannya dianggarkan bagi larutan tisu-GNP dengan ketumpatan 25 mg Au/g tisu prostat, dimodelkan sebagai campuran homogen. Daripada simulasi, dapatan kajian menunjukkan dos diserap sebanyak ~96 Gy daripada 98 benih, setiap satu daripada 0.31 mCi, 125I; ~102 Gy, dari 115 benih, setiap 1.4 mCi, dari 103Pd, dan ~90 Gy daripada benih 131Cs menggantikan benih 103Pd pada pemulaan aktiviti yang sama. Keistimewaan utama adalah 131Cs, ke atas 125I dan 103Pd, telah dilihat dalam kadar dos lebih besar (~26 cGy/hr) dikeluarkan pada pemulaannya iaitu dalam beberapa hari pertama iaitu 1.5 dan 5.7 kali lebih tinggi daripada 103Pd dan 125I. Dos yang diserap pada 125I, 103Pd dan 131Cs bertambah kepada ~245, ~130, ~187 Gy masing- masing dengan larutan tisu-GNP sebanyak 25 mg Au/g tisu. Hasil analisis menunjukkan penyerapan seumur hidup dos diserap pada ketiga-ketiga radioisotop dalam aturan yang sama, ini adalah keistimewaan menggunakan 131Cs; keistimewaan ini akan terus diuji pada masa depan dan diukur kuantitinya. KEYWORDS: Monte Carlo; simulation; medical; prostate cancer therapy; gold nanoparticles; dose enhancement 1. INTRODUCTION Cancer cases globally are expected to grow from 14.1 million in 2012 to 24 million by 2035 [1, 2] with the top three: lung [3], prostate [4-6], and colorectal cases accounting for over 47% of all cancers in men. The treatments for cancer, in order of general preference, are chemotherapy, surgery, and radiation therapy. In the case of recurrent cancers however, brachytherapy is the preferred treatment due to its localized and non- invasive effects. For brachytherapy, radioisotopes with energy <50 keV, such as 125I and 103Pd sources [7-9] with typical implants of 50-80 metallic seeds encasing isotopes, are used as low dose rate (LDR) [10] therapies for the treatment of prostate cancer, uveal melanomas and brain tumours. The dose is estimated by a number of computer codes such as EGSnrc, GEANT[11], PENELOPE [12] and MCNP [13] based on Monte Carlo (MC) methods [14]. Further improvements in the effectiveness of brachytherapy are being considered by the injection of gold nanoparticles through fenestrations of cancer cells. The particle size requirements are in the nanoscale range (~10-9 m) which is comparable with the diameter of an atom (~10-10 m) [15, 16]. For MC simulations in brachytherapy, it has been demonstrated that DEF is a function of the source energy and concentration of GNP solution [17-20], while the size of GNPs is not so important (above the K-edge energy). Thus, in this work, a homogenous model with considerable savings on the computational effort, required for a full heterogeneous model, is used to extract crucial information on the DEF resulting from the presence of gold in small concentration while MCNP has the capability of modelling very detailed heterogeneous configurations. This paper considers a homogenous model solely for the purpose of carrying out a comparative study for the dose delivered to a prostate tumour by 125I, 103Pd and 131Cs and particularly the enhancement of radiation dose due to the presence of gold. 177 Khan et al. IIUM Engineering Journal, Vol. 20, No. 2, 2019 https://doi.org/10.31436/iiumej.v20i2.1136 The ultimate goal of brachytherapy is to deliver maximum dose to the tumour while minimizing collateral damage to the normal tissue and for maximizing the DEF, there is still no consensus on the optimal size, shape and distribution of GNPs. However, experimental and pre-clinical evidence for mouse tumours, showing a 1-year survival rate of 86% following a dose of 26 Gy with 1.9 nm intravenously administered GNPs vs 20% for tumours not laden with GNPs [15], indicate that nanotechnology offers promising improvements in brachytherapy. The radioisotope cesium-131 (131Cs), was introduced to brachytherapy in 2004 [21] and in the first five years it was used in about 3000 prostate implants yielding the required dose in less time compared with 125I and 103Pd due to its shorter half-life and high energy, as shown in Table 1. Table 1: Energy and half-life of 125I, 103Pd and 131Cs Radionuclide E (keV) T1/2 (days) 103Pd 20.8 17 125I 35.49 59.4 131Cs 29-30.4 9.7 Typically,125I is used with a radiation dose of 145 Gy or more conforming to the prescribed dose of 145 Gy suggested by the American Association of Physicists in Medicine Task Group 64 [22]. While all three are low-energy sources, so that their dose would not extend to normal tissue in nearby organs [23], one of the main advantages of 131Cs is that it offers an initial dose rate of ~32 cGy/h at the periphery [24] which is 1.5 and 4 times higher than that from 103Pd and 125I respectively. This initial dose rate advantage is a vital radiobiological parameter for rapidly growing tumours [25] as well as for slow-growing tumours such as prostate adenocarcinomas. A set of clinical recommendations for prescribed doses, on the basis of 1200 prostate implants [26] indicated that the high initial dose rate of 131Cs caused more intense urinary and rectal complication but they also resolved more quickly than that for 125I and 103Pd. That study also found that the drop in prostate-specific antigen levels from 131Cs, with a maximum follow-up of just over three years and median follow-up of 23 months, were equivalent to that from other isotopes. Such promising results from 131Cs extended its use to gynecological malignancies [27] and to brain radiotherapy [28] from which it was demonstrated that this treatment was well-tolerated and safe for patients. 2. MATERIALS AND METHODS 2.1 Monte Carlo Simulation The Monte Carlo code MCNP5 is used to carry out a coupled photon-electron simulation of radiation transport in the range 1 keV-100 MeV to estimate the radiation dose distribution for prostate tumor brachytherapy. The radioisotope sources considered are 125I, 103Pd and 131Cs in the form of ‘seeds’ modelled as point sources. For 125I, 98 seeds each of 0.31 mCi and for 103Pd 115 seeds each of 1.4 mCi were spatially distributed in the tumour tissue, as shown in Fig. 1 [29] for data given for two patients with different size prostates. The placement of needles takes into account a number of factors including the location of vital organs surrounding the prostate, such as the bladder, urethra, and rectum. 178 Khan et al. IIUM Engineering Journal, Vol. 20, No. 2, 2019 https://doi.org/10.31436/iiumej.v20i2.1136 For simulating the effect of 131Cs, the 103Pd seeds were replaced by 131Cs seeds of the same initial activity and spatial distribution. The energy deposition track length estimation tally F6 and the pulse height tally *F8 are both used for estimating energy deposition to get reliable estimates in case of a few interactions in a region of interest. The simulation is repeated with gold-tissue solution; material compositions for both simulations are listed in Table 1. The photon and electron data for both tissue and gold are based on ENDF/B-VI (Release 8). In MCNP the “detailed physics” simulation incorporates coherent (Thomson) scattering and fluorescent photons produced from photoelectric absorption. Electrons produced from photon collisions are transported in a “condensed history” method that accumulates the effects of many individual collisions into single steps sampled probabilistically. The effects of such artefacts for electron transport have been investigated [30-32] with EGSnrc, GEANT and PENELOPE codes and in some cases “large discrepancies” (>3%) have been found between MCNP5 dose distributions and the ‘reference codes’ concluding that MCNP5 electron transport calculations are not accurate at all energies and in every medium by general clinical standards. It can thus be anticipated that MCNP5 may differ due to its inadequate low-energy treatment of electron transport. Authors of [33] have carried out electron transport comparisons of MCNPX, Penelope and EGSnrc, for electrons of 20-450 keV in water, lead, and tungsten. These comparisons were focused on bremsstrahlung, energy deposition in matter, electron ranges and production of secondary electrons by gamma radiation. Fig. 1: Placement of 25 needles with 98 seeds of 125I in the x-y plane. -5 -4 -3 -2 -1 0 1 2 3 4 5 -5 -4 -3 -2 -1 0 1 2 3 4 5 125I seeds x(cm) y (c m ) 179 Khan et al. IIUM Engineering Journal, Vol. 20, No. 2, 2019 https://doi.org/10.31436/iiumej.v20i2.1136 Fig. 2: Placement of 29 needles of 115 seeds of 103Pd/131Cs in the x-y plane. The F6 tally for dose from MCNP is converted from MeV/g to yield the dose rate in Gy/hr by using the activity as shown below. 2.2 Activity and Transformations The activity of a radioisotope is and the number of transformations in an interval is thus (1) Thus the ‘infinite-time’ transformations i.e. the number of disintegrations integrated over the time interval is . The absorbed dose is computed as follows: (2) where is the initial activity, N is the number of radioisotope seeds, and is the energy pulse height (*E8) tally (MeV) and m is the mass of the tumor (g). Thus, the absorbed dose varies directly with the energy deposition and source, which in turn depends on the number of transformations i.e. the product of initial activity and half- life. -5 -4 -3 -2 -1 0 1 2 3 4 5 -5 -4 -3 -2 -1 0 1 2 3 4 5 103Pd seeds x(cm) y (c m ) 180 Khan et al. IIUM Engineering Journal, Vol. 20, No. 2, 2019 https://doi.org/10.31436/iiumej.v20i2.1136 3. RESULTS MCNP simulations were carried out on an Intel(R) Core (TM) i7-2620M CPU @ 2.70GHz with an installed memory of 8.00 GB (3.24 GB usable) and 32-bit Operating system with Windows 7 Professional. The runtime for each simulation of 107 source particles was 35.60, 51.1 and 41 minutes for 125I, 103Pd and 131Cs, respectively The time-dependent transformations and activities of 125I, 103Pd and 131Cs, for an initial activity of 1 mCi each, are shown in Fig. 3. The basic hypothesis for effectiveness of each isotope arises from its half-life. This factor results in a longer decay time for 125I while faster decay rates of 103Pd and 131Cs translate into lifetime transformations of 2.74 × 1014, 7.84 × 1013 and 4.47 × 1013 for 125I, 103Pd and 131Cs respectively which clearly illustrate the slow build-up, but higher dose from 125I after ~ six months compared with the much faster effects of 103Pd and 131Cs. There is hence a saturation in activities for 103Pd and 131Cs with the implications that the effect of these two isotopes is seen much faster than that for 125I. Figure 4 shows the absorbed dose for 125I (initial activity 0.31 mCi, 98 seeds distributed as illustrated in Fig. 1), 103Pd and 131Cs (both of initial activity 1.4 mCi 115 seeds distributed as illustrated in Fig. 2) which indicates that 131Cs is clearly the best in terms of delivering the highest and fastest dose to the tumour, reaching 50 Gy in the first 10 days and 100 Gy when GNPs in a solution of 25 mg/g tissue are injected in the tumour. The absorbed dose on a longer timescale, however, is highest for 125I with GNP solution but exceeds that from 131Cs after about three months. For the sake of comparison, when all seeds are of equal initial activity (1.4 mCi) and placed in the configuration of Fig. 2, it is seen in Fig. 5 that the highest absorbed dose for both cases, with and without GNP- solution, is the highest at 117 Gy and ~283 Gy respectively but after ~250 days). Thus for a given requirement, 125I exceeds the 103Pd dose in about 200 days; higher doses for stronger tumours can thus not be treated by 131Cs and 103Pd unless they are used in conjunction with gold solutions. Fig. 3: Transformations and activity of 125I, 103Pd and 131Cs each of initial activity 1 mCi. 0 20 40 60 80 100 120 140 160 180 0 1 2 3 4 x 10 14 125I 125I 103Pd 103Pd 131Cs 131Cs T ra n sf o rm a tio n s Time (days) 0 20 40 60 80 100 120 140 160 180 0 2 4 x 10 7 0 20 40 60 80 100 120 140 160 180 0 1 2 3 4 x 10 7 0 20 40 60 80 100 120 140 160 180 0 1 2 3 4 x 10 7 A ct iv ity Ao=1 mCi 181 Khan et al. IIUM Engineering Journal, Vol. 20, No. 2, 2019 https://doi.org/10.31436/iiumej.v20i2.1136 Fig. 4: Absorbed dose (Gy) as a function of time (days) in prostate tissue from 98 seeds each of 0.31 mCi of 125I, 115 seeds each of 1.4 mCi of 103Pd and 115 seeds each of 1.4 mCi 131Cs (replacing 103Pd seeds). Fig. 5: Absorbed dose (Gy) as a function of time (days) in prostate tissue from 125I, 103Pd and 131Cs (115 seeds each of 1.4 mCi distributed as in Fig. 2) On a shorter time scale, the differences between all three isotopes is seen from the absorbed dose rates shown in Fig. 6 showing a clear advantage of 131Cs over the first ~300 hours exceeding 5.7 times and 1.5 times that of 125I and 103Pd respectively in the initial period and falling gradually, as shown in Fig. 7. Levelling off is found to be ~300 and ~400 hours respectively for 103Pd and 125I. 10 -1 10 0 10 1 10 2 10 3 0 50 100 150 200 250 Time (days) A bs D os e (G y) 125I 125I GNP 103Pd 103Pd GNP 103Cs 103Cs GNP 10 -1 10 0 10 1 10 2 10 3 0 50 100 150 200 250 300 Time (days) A bs D os e (G y) 125I 125I GNP 103Pd 103Pd GNP 103Cs 103Cs GNP 182 Khan et al. IIUM Engineering Journal, Vol. 20, No. 2, 2019 https://doi.org/10.31436/iiumej.v20i2.1136 Fig. 6: Absorbed dose rate (Gy/hr) as a function of time (hours) in prostate tissue from 98 seeds each of 0.31 mCi of 125I, 115 seeds each of 1.4 mCi of 103Pd and 115 seeds each of 1.4 mCi 131Cs (replacing 103Pd seeds). Fig. 7: Relative absorbed dose rate (Gy/hr) of 131Cs (relative to 125I and 103Pd) as a function of time (hours) in prostate tissue from 98 seeds each of 0.31 mCi of 125I, 115 seeds each of 1.4 mCi of 103Pd and 115 seeds each of 1.4 mCi 131Cs (replacing 103Pd seeds). The lifetime dose delivered by the three sources considered is shown in Table 2. The absorbed dose for 125I, 103Pd and 131Cs increases from 96.30, 102.21 and 90 Gy to ~245, ~130, ~187 Gy with GNP-tissue solution of 25 mg Au/g tissue. These results are in line 10 0 10 1 10 2 10 3 10 4 0 0.05 0.1 0.15 0.2 0.25 0.3 0.35 Time (hours) A bs D os e R at e (G y/ hr ) 125I 103Pd 103Cs 10 0 10 1 10 2 10 3 10 4 0 1 2 3 4 5 6 Time (hours) R el . A bs D os e R at e of 13 1 C s 103Pd 125I 183 Khan et al. IIUM Engineering Journal, Vol. 20, No. 2, 2019 https://doi.org/10.31436/iiumej.v20i2.1136 with the decay rates of the three isotopes which favour 125I in terms of energy but result in a slow dose delivery. The dose enhancement with gold GNP-tissue found in these simulations is the effect of both source energy of each radioisotope and the solution concentration. The important photon interaction for high-Z materials such as gold is the photoelectric effect for which the cross-section varies as so that low energy and high-Z are desirable for dose enhancement which is localized to the tumor due to the short range of photoelectrons and Auger electrons in the surrounding medium which for electrons of energy 0.1 MeV is ~100 microns in water and ~15 microns in gold so that the effect of gold will require thin layers (of the order of to utilize the energy of photoelectrons in water. At this energy, the photoabsorptions were estimated to be ~13.5% of all interactions. Thus, the increases found in this work are a measure of the photon interaction in each radioisotope. As shown in Table 2, the highest dose achievable is ~245 Gy by 125I, and lesser doses by 103Pd and 131Cs for 25 mg Au/g tissue. When the configuration of Fig. 2 is used for all three sources of 1.4 mCi each, the F6 and F8 tallies for 125I increase to 1.82733 × 10-5 (0.0011) MeV/g and 1.24662 × 10-3 (0.0016) MeV respectively, as depicted in Fig. 5. Table 2: Lifetime absorbed dose (Gy) to prostate tumour due to 125I, 103Pd and 131Cs. The second result in F6, F8 and Abs. Dose columns refer to Tissue with 25 mg Au/g tissue homogenous mixture Source T1/2 (d) A0 (mCi) E(kev) Nseeds Tr=A0/ (s-1) F6 (rel. err.) (MeV/g) F8 (rel. err.) (MeV) Abs. Dose* (Gy) 125I 59.4 0.31 35.49 98 8.5 × 1013 1.73548 × 10-5 (0.0011) 4.30593 × 10-5 0.0012 1.183 × 10-3 (0.0016) 3.0087 × 10-3 0.0010 96.30 244.91 103Pd 17 1.4 20.8 115 1.1 × 1014 1.21460 × 10-5 (0.0018) 1.50096 × 10-5 0.0019 8.2786 × 10-4 (0.0015) 1.0511 × 10-3 0.0014 102.21 129.77 131Cs 9.7 1.4 30.4 115 6.3 × 1013 1.88145 × 10-5 (0.0012) 3.79186 × 10-5 (0.0013) 1.2803 × 10-3 (0.0015) 2.64847 × 10-3 0.0010 90.17 186.57 *for an organ mass 16.3634 g 4. CONCLUSIONS From the simulations, it was concluded that: lifetime absorbed dose is ~96 Gy from 98 seeds, each of 0.31 mCi, of 125I, ~102 Gy, from 115 seeds, each of 1.4 mCi, of 103Pd, and ~90 Gy from 131Cs seeds replacing 103Pd seeds of the same initial activity, there is a saturation in the activities of 103Pd and 131Cs with the implications that the effect of these two isotopes is much faster than that of 125I, the main advantage of 131Cs, is the larger initial dose rate (~26 cGy/hr) for the first few days, which is 1.5 and 5.7 times higher than that for 103Pd and 125I, 184 Khan et al. IIUM Engineering Journal, Vol. 20, No. 2, 2019 https://doi.org/10.31436/iiumej.v20i2.1136 with a GNP-tissue mixture, the dose enhancement factors in 125I, 103Pd and 131Cs are 2.5, 1.26 and 2.1 respectively which give another edge to 131Cs, for a specified dose, 125I exceeds 103Pd by about 200 days; higher doses for stronger tumours can thus not be treated by 131Cs and 103Pd unless they are used in conjunction with gold solutions. This work has shown results for three candidate radioisotopes in their effectiveness for the treatment of tumours. The basic hypotheses to determine their effectiveness were their radiation energy and half-life. The Monte Carlo simulations carried out in this work have elaborated the effect of radiations from three isotopes and found substantially higher time of treatment, as well as stronger radiation dose with 125I than for 103Pd and 131Cs. 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Applied Radiation and Isotopes, 68(4-5): 961-964. doi: 10.1016/j.apradiso.2009.12.019. 187 << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles false /AutoRotatePages /None /Binding /Left /CalGrayProfile (Gray Gamma 2.2) /CalRGBProfile (None) /CalCMYKProfile (None) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Warning /CompatibilityLevel 1.7 /CompressObjects /Off /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJobTicket false /DefaultRenderingIntent /Default /DetectBlends true /DetectCurves 0.0000 /ColorConversionStrategy /LeaveColorUnchanged /DoThumbnails false /EmbedAllFonts true /EmbedOpenType false /ParseICCProfilesInComments true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 1048576 /LockDistillerParams true /MaxSubsetPct 100 /Optimize false /OPM 0 /ParseDSCComments false /ParseDSCCommentsForDocInfo false /PreserveCopyPage true /PreserveDICMYKValues true /PreserveEPSInfo false /PreserveFlatness true /PreserveHalftoneInfo true /PreserveOPIComments false /PreserveOverprintSettings true /StartPage 1 /SubsetFonts false /TransferFunctionInfo /Remove /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /CropColorImages true /ColorImageMinResolution 200 /ColorImageMinResolutionPolicy /OK /DownsampleColorImages true /ColorImageDownsampleType /Bicubic /ColorImageResolution 300 /ColorImageDepth -1 /ColorImageMinDownsampleDepth 1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages true /ColorImageFilter /DCTEncode /AutoFilterColorImages false /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /ColorImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 15 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 15 >> /AntiAliasGrayImages false /CropGrayImages true /GrayImageMinResolution 200 /GrayImageMinResolutionPolicy /OK /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 300 /GrayImageDepth -1 /GrayImageMinDownsampleDepth 2 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages false /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /GrayImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 15 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 15 >> /AntiAliasMonoImages false /CropMonoImages true /MonoImageMinResolution 400 /MonoImageMinResolutionPolicy /OK /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 600 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /CheckCompliance [ /None ] /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputConditionIdentifier () /PDFXOutputCondition () /PDFXRegistryName () /PDFXTrapped /False /CreateJDFFile false /Description << /ARA /BGR /CHS /CHT /CZE /DAN /DEU /ESP /ETI /FRA /GRE /HEB /HRV /HUN /ITA (Utilizzare queste impostazioni per creare documenti Adobe PDF adatti per visualizzare e stampare documenti aziendali in modo affidabile. 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