Phenotypic Characterization of Patients with Polycystic Ovary Syndrome in a Population from the Ecuadorian Andes: A Cross-Sectional Study

REVIEW Complementary and Alternative Medicine to Treat Fibromyalgia Symptoms. A Systematic Review Barbara Badanta 1, *, Isabel Álvarez-Pérez 2 , Patricia Bonilla Sierra 3 , María González-Cano-Caballero 4, *, Giancarlo Lucchetti 5 , Rocío de Diego-Cordero 1, * 1 Department of Nursing; Faculty of Nursing, Physiotherapy and Podiatry, University of Seville, Seville, Spain; 2 Faculty of Nursing, Physiotherapy and Podiatry. University of Seville, Seville, Spain; 3 Department of Health Sciences, Universidad Técnica Particular de Loja (UTPL), Loja, Ecuador; 4 Department of Nursing; Faculty of Health Sciences, University of Granada, Granada, Spain; 5 Department of Medicine; School of Medicine, Universidade Federal de Juiz de Fora, Juiz de Fora, Brazil *These authors contributed equally to this work Correspondence: María González-Cano-Caballero, Department of Nursing, Faculty of Health Sciences, University of Granada, Av. de la Ilustración, 60, Granada, 18071, Spain, Email [email protected] Abstract: This study aims to investigate the current evidence for the use of complementary and alternative medicine (CAM) in fibromyalgia (FM). A systematic review was conducted searching for PubMed, Scopus, CINAHL, PsycInfo, and Web of Science databases. Randomized controlled trials published up to December 2023 in peer-reviewed journals were included. Methodological quality was assessed by the Quality Assessment of Controlled Intervention Studies tool. A total of 216 articles were identified and 15 constituted the final sample. The type of CAM most used was traditional Chinese medicine (60%), and the most common instrument used was the Fibromyalgia Impact Questionnaire (60%). Our review was grouped into four themes based on the origin of the therapies: 1) Traditional Chinese Medicine; 2) Japanese natural harmonization (eg, Reiki); 3) Ayurvedic Medicine; and 4) Other nondrug therapies. Our systematic review showed that there is a wide range of CAMs used to treat FM. Most of the clinical trials have shown significant results for the effectiveness of these interventions in both physical and mental health outcomes of FM as compared to control groups. However, the heterogeneity of the interventions and outcomes warrants further studies on this topic. Keywords: complementary therapies, fibromyalgia treatment, nonpharmacological interventions, traditional medicine Introduction The Fibromyalgia (FM) is a chronic disease characterized by the presence of generalized chronic pain, skin hypersensitivity, fatigue, gastrointestinal symptoms, sleep problems, and cognitive and psychological impairments (ie, higher prevalence of anxiety and depression). 1,2 The diagnosis of FM is based predominately on the presence of chronic pain, as established by the American College of Rheumatology (ACR), which includes chronic widespread pain in at least 4 of 5 regions and for a minimum of three months. Likewise, they should present a Widespread Pain Index (WPI) ≥7 and Symptom Severity Scale (SSS) score ≥5 OR a WPI of 4–6 and SSS score ≥9. 3 Since diagnosis is based on clinical tests and not accompanied by laboratory or radiological tests, FM is still underdiagnosed. 3,4 Other multiple factors contribute to this underdiagnosis, such as stigmatization due to gender issues (eg, FM considered a ‘disease of females’), 5 and the heterogeneity of diagnostic criteria and their updates and suggestions (ie, 1990, 2010, 2011 and 2016). 1 The most common treatment offered to these patients is pharmacological treatment (ie, opioid analgesics, antiinflammatory medications, antidepressants). However, many of these drugs have important adverse effects and do not completely alleviate the symptoms of patients. 6 Other commonly used therapies for FM are physical exercise (aerobic and resistance training) and lifestyle, which proved to be effective in the literature as well. 7 Despite these therapies, the difficulty in diagnosing FM together with the social, cultural, psychological, and functional impact that it produces makes patients search for complementary and alternative medicine (CAM) to improve their quality of life. 2 Journal of Pain Research 2024:17 1709–1723 1709 © 2024 Badanta et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Journal of Pain Research Dovepress open access to scientific and medical research Open Access Full Text Article Received: 20 November 2023 Accepted: 22 April 2024 Published: 10 May 2024 Journal of Pain Research downloaded from https://www.dovepress.com/ For personal use only. It is important to understand that since 2014, World Health Organization (WHO) has supported proactive policies and implementing action plans that will strengthen the role traditional medicine plays in keeping populations healthy. 8 However, the definition of CAM is not homogeneous. In some cases, the concept of complementary medicine is equated with traditional, holistic, or alternative medicine. 9 These are unconventional practices used together or not with conventional pharmacological medicine. 6 Therefore, this work will use the WHO definition of CAM as follows: “health care practices that are not part of conventional medicine in a country and are not fully integrated into the dominant health care system”. 10 CAM therapies are usually divided into domains such as: whole medical systems (eg, acupuncture), mind-body medicine (ie, spiritual, meditative, and relaxation techniques), biologically based systems (eg, vitamins and natural products), manipulative and body-based practices (eg, massage, chiropractics, and osteopathy), and (5) energy medicine (eg, Reiki therapy). 11 In recent years, some authors have described the beneficial effects of CAM in FM patients, showing that between 90 and 98% of patients have used them in the previous year to reduce their symptoms. 12,13 Two previous systematic reviews have supported the role of homeopathy and herbal/diets in improving pain at ‘tender points’, sleep quality and mood. 14,15 Other CAM therapies such as tai chi and meditation also reflected improvements in the quality of life of these patients, 16 while acupuncture reduced pain, fatigue, sleep disturbances, and emotional rigidity. 13 Although Perry et al have identified some evidence to support the effectiveness of acupuncture for FM, other CAM strategies had limited evidence, highlighting the need for an updated compilation of studies. 17 Furthermore, there are several barriers to the implementation of these therapies in clinical practice, such as negative beliefs of physicians and patients, lack of training in nursing and medical courses, and lack of time. 18,19 This systematic review aims to better understand these therapies, providing an updated overview of the field and investigating the current evidence for the use of CAM in fibromyalgia. Materials and Methods Design A systematic review of randomized controlled trials (RCT) assessing CAM interventions as a treatment of fibromyalgia was carried out, following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines (Supplementary Material 1). 20 The protocol was previously registered in PROSPERO: blinded. The main research question was: What non-pharmacological treatments have been studied for persons with fibromyalgia? What is their current evidence of effectiveness? Search Strategy The search was carried out independently by two researchers up to December 2023 in PubMed (https://pubmed.ncbi.nlm. nih.gov), Scopus, CINHAL, PsycINFO, Web of Science databases, using the following search strategy: (fibromyalgia [title] OR “fibromyalgia treatment”) AND (“nonpharmacological treatment” OR “traditional Chinese medicine” OR “traditional medicine” OR “traditional medicine” OR “alternative medicine” OR “complementary medicine” OR “cultural practice”). The research question was elaborated following the PICOTS structure (Table 1). Inclusion and Exclusion Criteria Original articles published up to December 2023 in peer-reviewed journals were included, with no restrictions of language and geographical setting. Randomized controlled trials addressed the use and effects of non-pharmacological therapies in patients with fibromyalgia were accepted. However, non-randomized and/or non-controlled quantitative or qualitative studies were excluded. Furthermore, opinion articles, editorials, comments, doctoral theses, synthesis of literature publications, and those related to chronic pain from cancer and other pathologies were also excluded. https://doi.org/10.2147/JPR.S450735 DovePress Journal of Pain Research 2024:17 1710 Badanta et al Dovepress Powered by TCPDF (www.tcpdf.org) Study Selection and Data Extraction After searching the literature, all references were included in Mendeley Software 1.19.18. The initial screening was carried out by two reviewers independently reading titles and abstracts. Duplicate publications were also excluded in this phase. Subsequently, the selected articles were subjected to a full-text reading. Finally, the main characteristics of the selected articles were extracted and presented in a table, taking into account the geographic area of the study, the therapy used, the purpose, methods, the instruments, the number of sessions/duration, the follow-up, the results compared to the control group and other findings, as well as the methodological quality of each study. Quality Assessment The studies that met the inclusion criteria were assessed by two reviewers independently for methodological validity prior to inclusion in the review. Any disagreements between the reviewers were resolved by a third reviewer. The Quality Assessment of Controlled Intervention Studies 21 was used to assess the reporting of randomized controlled trials (Supplementary Material 2). Development of Themes To answer the research questions for this systematic review, a thematic analysis approach was taken. 22 The reviewers participating in searches, selection, article evaluation, and data extraction organized descriptive labels, focusing on emerging or persistent therapies, their similarities, or differences in using them and their effects. Results The search process identified 216 publications that matched the search criteria (Figure 1). After removing duplicates, 196 articles remained, of which another 119 articles were excluded after screening the titles and abstracts. A total of 77 articles underwent full-text analysis, and the final sample included 15 randomized controlled trials. Characteristics of the Included Studies A total of 15 articles were included in the systematic review, 66.6% of them published in the last ten years (n = 10). Most of the studies were developed on the American continent (n = 11; 73.3%) – mostly in the USA (North America, n = 6) and Brazil (South America, n = 4). The mean age of the participants in these studies was 45 years, and the women were the only participants in 53.3% of the publications. The type of CAM most used was related to traditional Chinese medicine (TCM) (60%), and the efficacy of the different therapies was measured using instruments such as the Fibromyalgia Impact Questionnaire (FIQ) (60%), Visual Analog Scale (VAS) (40%), and Short Form 12 or 36 Health Survey Questionnaires from the Medical Outcomes Study (SF-12, SF-36) (40%). Quality assessment revealed that most studies asked appropriate research questions and had clearly defined populations, good response rates, similar populations, appropriate exposure and outcome variables, and controlled for confounders (see Supplementary Material). Table 1 PICOTS (Population, Intervention/Exposure, Comparator, Outcome, Time, and Study design) Criteria PICOTS Criteria Population Patients diagnosed with fibromyalgia according to criteria of the American College of Rheumatology (ACR) Intervention/Exposure Complementary and Alternative medicine interventions Comparator Standard practice, sham intervention or no comparator Outcome Relief of physical and/or mental symptoms related to fibromyalgia Time Not Applicable Study design Controlled trials Journal of Pain Research 2024:17 https://doi.org/10.2147/JPR.S450735 DovePress 1711 Dovepress Badanta et al Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) Our analysis of the findings of the articles was grouped into four themes based on the origin of the therapies: 1) Traditional Chinese Medicine; 2) Japanese natural harmonization; 3) Ayurvedic Medicine; and 4) Other non-drug therapies (Table 2). Traditional Chinese Medicine As part of TCM, two randomized controlled trials with 36 and 30 women, respectively, determined the effectiveness of acupuncture in FM, showing an improvement in the global impact of FM and a reduction of fatigue and pain immediately Figure 1 Flowchart for the selection of articles for the systematic review. Adapted from Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. 20 https://doi.org/10.2147/JPR.S450735 DovePress Journal of Pain Research 2024:17 1712 Badanta et al Dovepress Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) Table 2 Description of Complementary and Alternative Therapies Used to Treat Fibromyalgia Theme Non-Pharmacological Therapies Description Traditional Chinese Medicine Acupuncture Insertion of metallic needles in special points of the skin. The body is made up of meridians or channels, corporal routes that connect each part from head to toe and from left to right. They transport qi and blood and regulate the yin and yang flow, keeping the functions and activities of all body parts in harmony. Acupuncture is combined with moxibustion on many occasions. Moxibustion Moxibustion is a modality of traditional acupuncture that involves burning moxa, the herb Artemisia vulgaris, on or above the skin, warming them to alleviate symptoms. The most commonly used practice is indirect moxibustion, in which the moxa is burned placed on top of the acupuncture needle. Tai Chi Traditional self-healing, self-cultivation exercises originating in China. They are based on coordinated body posture, slow and low-impact movements, deep rhythmic breathing, meditation, and mental focus (attention to interoceptive sensations instead of aversive thoughts and impulses. They favor the flow of vital energy or “Qi” and influence the spiritual and physical state and stress. GanodermaLucidum (fungi) Fungi used for clinical prevention and treatment of diseases, especially for the middle-aged and elderly population. Ganoderma spores powder has the effect of regulating immunity, antitumor, antioxidation, and protecting cells. It is traditionally administered as a decoction, in tea or coffee. Japanese natural harmonization Reiki Biofield energy therapy that offers whole-person healing of body, mind, and spirit. Reiki therapy is characterized by spiritual practice without any references to religion in which the practitioner guides the energy to a living receiver (ie person, animals, or flora). Its effects on pain and psychological well-being have been explored. Ayurvedic medicine Yoga Mind body intervention that combines specific physical postures (asanas), breathing techniques (pranayama), relaxation and meditation to encourage union of mind and body. Yoga consists of eight limbs: yama (ethical behavior), niyama (personal behavior), asana (physical posture), pranayama (breath regulation), pratyahara (sensory inhibition), dharana (concentration), samadhi (integration), dhyana (meditation). Other non-drug therapies Balneotherapy Mineral-medicinal waters in contact with the skin at different temperatures, being able to achieve therapeutic effects (eg, analgesia, increased enzyme activity, muscle relaxation, increased of pain threshold). Animal assisted therapy Interaction between humans and animals at home (pet ownership) or in healthcare settings with therapist-led interventions. The most commonly used animals are dogs and horses and both animals and therapists require prior training. Training includes activities of daily living such as feeding the animal, motor skills, planning, and social and communication skills. Diet therapy: Soy Basic food ingredient of traditional Asian cuisine belonging to Fabaceae family. Soy has high protein from plant sources and versatility in the production of meat analogues and milk substitutes. Furthermore, soybeans contains isoflavones, unsaturated fatty acids, B vitamins, fibre, iron, calcium, zinc and other bioactive compounds. Music therapy Music can have a positive effect on the physiological and psychological state due to its effects on both distraction and relaxation about pain. In addition, preferred music produces pleasant emotions and activates stress reduction mechanisms, such as reward-related circuits (dopamine release). Journal of Pain Research 2024:17 https://doi.org/10.2147/JPR.S450735 DovePress 1713 Dovepress Badanta et al Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) after the intervention. 23,24 Another study with 120 patients with FM allocated randomly to four groups (30 patients each) combined music with vibration on acupuncture points and also obtained positive results. 25 The results of acupuncture persisted in the long term, not only decreasing the sensitivity to tender points but also significantly improving depression and anxiety and the performance of social roles. 26,27 However, in the results of Harris et al, 28 although overall pain improvement was observed with 25–35% of subjects, no additional beneficial effects were found, both applying acupuncture, electroacupuncture, and manual stimulation. The combination of acupuncture and electroacupuncture with other methods to relieve chronic pain as moxas 26 showed little significant differences in pain reduction, but positive results in vitality and mental health in patients. Oral ingestion therapies are also addressed by the TCM, such as the use of Ganoderma Lucidum mushroom (also called Reishi). Pazzi et al 29 investigated its effects on depression, happiness, life satisfaction, and quality of life among patients with fibromyalgia. Although observing a trend towards long-term improvement in happiness, life satisfaction, and depression levels in patients treated with the fungus once a day for 6 weeks, this supplement did not report significant differences between the two groups. Other TCM therapies are those related to body movements. Tai Chi improved the quality of sleep, the global health (physical and mental) of the patient, and the values of the values of the FIQ scale, both during the study, at the end of the treatment, and up to 6 months later. However, this did not improve the self-efficacy of chronic pain. 30 Japanese Natural Harmonization Derived from traditional Japanese medicine, Aseffi et al 31 used Reiki as a therapy to control pain. However, there were no statistically significant differences between the control and the experimental group for pain values measured through the VAS scale and the global health status of SF-36 and neither chronic fatigue nor physical or mental well-being improved. Ayurvedic Medicine Ayurvedic medicine has been one of the Indian complementary therapies applied to patients with FM in order to achieve a balance between body, mind and spirit. Yoga was used as a technique to achieve meditation and mental concentration. Therefore, Da Silva et al 32 analyzed the effectiveness of Yoga combined with Tui Na applied during 8 weekly sessions and both treatment groups with a significant decrease in the values of the global impact of FM after treatment, as well as a decrease in pain, which was maintained long term only in the group that practiced yoga. Other Non-Drug Therapies One of the western therapies used to treat rheumatic diseases is balneotherapy, from the Greek origin. Koçyiit et al 33 determined its positive effect on the impact of FM, the count of tender points and perceived pain after 21 sessions. However, after 6 months, only significant improvements in the impact of FM and the level of pain were maintained. Kurt et al 34 have also used balneotherapy for FM but now combined with physical exercise. They found that improvements in sleep quality were added to the beneficial results already indicated. However, only the group that only did physical exercise significantly improved depression levels. Another study explored the effects of animal-assisted therapy (in this study the use of dogs). Although after interaction with dogs, some levels of the global impact of FM, positive feelings, pain levels, and physiological parameters (heart rate and oxytocin levels) improved, the differences between the groups in the trial were not statistically significant. 35 The results of a study conducted in Italy evaluated music therapy as a method to reduce pain perception, increase well-being, and improve quality of life. 36 These authors showed an improvement in mental well-being but not a significant effect on pain perception. Finally, mind-body therapies have been combined with the restriction or incorporation of nutritional elements. The intake of soy shakes once a day for 6 weeks as a dietary supplement was also not effective on the global impact or depression associated with FM. 37 More details of the results are shown in Table 3. https://doi.org/10.2147/JPR.S450735 DovePress Journal of Pain Research 2024:17 1714 Badanta et al Dovepress Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) Table 3 Results of the Evaluation of Non-Pharmacological Therapies for the Treatment of Fibromyalgia Reference Therapy Aim(s) Design a Eligibility criteria Participants Instrument b N° sessions/ duration (min) Follow-up Results compared to CG Main findings Brazil 23 Acupuncture To determine the therapeutic effectiveness of acupuncture on patients with FM. RCT – N=36 (CG=15; IG=21) Gender: 86% females. Mean age: 51 years. VAS 1/20 1 day + After the end of the treatment, significant improvements were shown in the immediate measurement of pain in the IG. USA 24 Acupuncture To test the treatment effect of acupuncture vs education in persons with FM. RCT Aged 18–75 years. Average pain of ≥ 5 on a VAS over the last week. Score of < 29 on the Beck Depression Inventory. N = 30 (IG=16; CG=14) Gender: 100% females. Mean age: 54 years. FIQR total, FIQR Pain, GFI 20/40 3 1/2 months +/+ FIQR total, FIQR Pain and GFI were significantly higher in the IG as compared to the CG at the end of treatment and after four weeks of follow up Panamá 25 Acupuncture and music To investigate the effect of music combined with vibration on acupuncture points for the treatment of FM RCT Aged: 30–60 years. Treatment recommended by the rheumatology service for a ≥ 6 months. N=120 (GC=30; GI=90 (G1- Vibration, G2- Music, G3- Combined Music +Vibration). Gender: 100% females. Mean age: 49 years. FIQ, HAQ. 5/30 20 days FIQ: N/ HAQ: + There were no differences concerning reduction in FIQ among groups. However there were differences on HAQ reduction among groups, favoring the combined group as compared to CG. Brazil 26 Acupuncture (AC), Electroacupuncture (EAC), Moxibustion (MX) To compare acupuncture, electroacupuncture and moxibustion in patients with FM. RCT Aged 20–60 years. N=30 (ACG= 10; EACG=10; MXG= 10) Gender: 100% females. Mean age: 46.9 years. WBFPS, SF-36. 8/30 2 months N/N No improvements were observed in pain and tender points, or in quality of life, but in the vitality and mental health of the participants. (Continued) Journal of Pain Research 2024:17 https://doi.org/10.2147/JPR.S450735 DovePress 1715 Dovepress Badanta et al Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) Table 3 (Continued). Reference Therapy Aim(s) Design a Eligibility criteria Participants Instrument b N° sessions/ duration (min) Follow-up Results compared to CG Main findings Brazil 27 Auricular Acupuncture To evaluate the effects of systemic electroacupuncture (EA) associated of auricular acupuncture for pain intensity, heart rate variability, and quality of life in fibromyalgia. RCT Women aged over 40 to 78 years and clinical diagnosed with fibromyalgia according to the 2010 criteria of the FDC. N=18 (CG=9; IG=9) Gender: 100% females Mean age: 57.5 years NPRS, FDC 2010, FIQ, and analysis of Heart Rate Variability 12 / 20 6 weeks N/N/+/N EA with systemic frequencies of 2/ 100 Hz and associated with the Nogier frequency (2.28, 4.56 and 9.12 Hz) in auricular acupuncture, reduced the impact of fibromyalgia, particularly in the domains of pain and anxiety. Regarding the NPRS variables, FDC 2010 and HRV, they remained unchanged. USA 28 Acupuncture To investigate whether typical acupuncture methods such as needle placement, needle stimulation, and treatment frequency are important factors in fibromyalgia symptom improvement. RCT Diagnosed with fibromyalgia for at least 1 year. Widespread pain on more than 50% of days. N=114 (IG: T/S=29; CG: T/0=30; N/ S=28; N/0=27) Gender: 93% females. Mean age: 47.25 years. NRS, MAF, SF- 36. 18/ 20 4 months All measures: N There was an improvement in the pain, fatigue and physical function scale, with no differences between groups. https://doi.org/10.2147/JPR.S450735 DovePress Journal of Pain Research 2024:17 1716 Badanta et al Dovepress Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org) Spain 29 Ganoderma lucidum (GL) mushroom To assess the effects of GL on happiness, depression, satisfaction with life, and health-related quality of life in women with FM. RCT Not taking immunosuppressants, vitamin C supplements or anticoagulants. N=64 (IG=32; CG=32) Gender: 100% females Mean age: 54.9 years SHS, SWLS, GDS, SF-12, GIIS. 42/ - 1 1/2 months N No significant differences were observed in the IG, although there was an improvement trend in the levels of happiness and satisfaction with life in the patients treated with this fungus. USA 30 Tai-Chi (Yang-style) To compare the physical and psychological benefits of tai chi with an intervention of education and stretching in patients with FM. RCT Aged ≥ 21 years N=66 (CG=33; IG=33). Gender: 86.3% females. Mean age: 50 years. FIQ, VAS, PSQI, CES-D, CPSS, SF-36. 24 / 60 6 months FIQ, VAS, PSQI, CES- D, SF-36: +/+ CPSS: N/N The FIQ score, sleep quality, the global health, physical and mental components improved in the IG after finishing the sessions at week 12, and it was maintained at week 24. However, there were no differences regarding chronic pain self-efficacy (CPSS). USA 31 Reiki To determine whether Reiki is beneficial as an adjunctive FM treatment. RCT Global pain score of ≥ 4 on VAS. Use ibuprofen / acetaminophen for breakthrough pain. N=100 (CG=50; IG=50) Gender: 92% females Mean age: 49 years VAS, SF-36 16 / 30 3 months N/N/N Reiki did not improve pain level, chronic fatigue, well-being, or physical / mental functioning. Brazil 32 Yoga and Tui Na To test the effects of a relaxing yogic practice (with and without the addition of Tui Na) on the impact of FM. RCT Aged: 25–60 years. N=33 (CG Tui Na=16; IG=17) Gender: 100% females. Mean age: 45.6 years VAS, FIQ. 8/ 50 7 weeks N/N The score on the FIQ and pain scale (VAS) decreased in both groups, without statistical significance in the IG. (Continued) Journal of Pain Research 2024:17 https://doi.org/10.2147/JPR.S450735 DovePress 1717 Dovepress Badanta et al Powered by TCPDF (www.tcpdf.org)Powered by TCPDF (www.tcpdf.org)