Influence of melatonin supplementation on tissue response of endodontic sealers in Wistar rats

Influence of melatonin supplementation on tissue response of endodontic sealers in Wistar rats | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Influence of melatonin supplementation on tissue response of endodontic sealers in Wistar rats Pedro Henrique Chaves de Oliveira, Michael Júnio da Silva Rodrigues, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3649915/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives: Evaluate the influence of melatonin supplementation on tissue’s response to endodontic sealers in Wistar rats. Material and methods: Forty-eight Wistar rats had four polyethylene tubes implanted in their subcutaneous tissue, one empty (control) and three filled with endodontic sealers (AH Plus, Endofill and Sealapex). Half of the animals were supplemented with melatonin (TM) and the remaining with water (TW) for 15 days before the implantation until euthanasia. After 5, 15 and 30 days (n=8/group/period) tubes were removed and analyzed in H&E, immunohistochemistry, PSR, VK and POL. The results were statistically analyzed (p<0.05). Results: In TW, Endofill evoked a more intense inflammatory infiltrate compared to AH Plus and control in 30-day (p0.05), differences for Endofill (p=0.05) and Sealapex (p<0.05) was observed in TM animals in 30-day, presenting lower inflammatory infiltrate. For IL-6 and TNF-α it was observed that the immunolabeling was lower in TM animals in all periods, despite of the sealer. In addition, there was a higher percentage of mature fibers in TM groups at 5 days (p<0.05). Structures positive for von Kossa staining and birefringent to polarized light were observed only for Sealapex in all periods, regardless of melatonin supplementation. Conclusion: Melatonin influences inflammatory response of endodontic sealers, by modulating the inflammatory process and pre-inflammatory mediators, and stimulating tissue repair, without interfering on calcium deposition. Clinical Relevance: Evidence that melatonin can regulate inflammatory responses after the contact of tissues with biomaterials. dodontic sealers tissue response inflammation mineralization melatonin Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The filling of the root canals is done by using endodontic sealers that along with the gutta percha allow the canal obturation [1]. In this context, an ideal endodontic sealer must present specific biological and physicochemical characteristics, such as biocompatibility and dimensional stability [2,3]. Different responses can be observed in tissues, depending on the sealer base compound [2-4]. Consequently, these reactions can influence periapical repair, inducing or even delaying it [5,6]. The ones based on oxide zinc, for example, can promote a more exacerbated inflammatory response, while others that contain different formulations induce lower inflammation, such as those based on calcium silicate, which also can induce the mineralization process [4,7,8]. The local inflammatory response can be modulated by different substances [9-11], one of them is melatonin (N-acetil-5-metoxitriptamine), an endogenous indolamine, produced in the absence of light by the pineal gland and other areas of the body, such as the retina, salivary gland and even inflammatory cells [12-14]. This indolamine performs different functions, such as chronobiological, immunomodulatory, sedative, antitumor, analgesic, anti-inflammatory and antioxidant functions [15-18]. As an anti-inflammatory agent, several studies have demonstrated that melatonin can regulate the inflammatory process ceasing innumerable events within the cell cascade by the signalling of NF-k β (Nuclear transcription factor – Kappa β) , which is translocated to the nucleus of cells, binding itself to specific elements that modulate the transcription of pro-inflammatory genes [19-24]. In addition, melatonin can influence the expression of pro-inflammatory and anti-inflammatory cytokines, and the recruitment of polymorphonuclear leukocytes to sites of inflammation in different pathophysiological situations [25, 26]. Besides, this substance is proven to be a regulator of inflammation in dental conditions, such as periodontitis diseases, mucositis and it can potentiate the repair process in teeth extractions, implants and periodontal areas [24]. Considering that endodontic sealers can develop local inflammatory reactions on connective tissues and that melatonin is a potential regulator of the inflammatory process, the present study evaluated the influence of melatonin supplementation on tissue’s response to endodontic sealers by a consolidated method of exploring the biomaterials response, the implantation of polyethylene tubes in subcutaneous tissues of Wistar rats [27]. Null hypothesis: Melatonin would not interfere with the tissue’s response to endodontic sealers. Material And Methods The manuscript of this animal study has been written according to Preferred Reporting Items for Animal studies in Endodontology (PRIASE) 2021 guidelines [28]. Experimental Animals Following the protocols of previous studies, using an alpha error of 0.05% and 95% power to recognize a significant difference of 1 in the median scores, a minimum of seven animals per group was considered necessary. Taking into consideration the possible complications that could occur during the study, one more animal was added to each group (TM and TW) in each experimental time. Considering three observation times, 48 animals were necessary in this study [4, 27, 29], They were caged in a controlled temperature and light cycle environment (22 ± 1 ° C, 70% humidity at 12 hours light and 12 hours dark), received solid diet and ad libitum water, except for the first 24 hours after the intervention. The experimental procedures were approved and performed according to the guidelines of the ethical committee (process no. 00433-2018). Melatonin supplementation Half of the animals were supplemented with melatonin (Group treated with melatonin – TM) and the other half with water (Group treated with water – TW). The supplementation occurred 15 days before the implantation of the endodontic sealers and lasted until the sacrifice day, as a therapy supplementation. The dose of melatonin was 10mg/kg/day dissolved in 1 % ethanol and 1 ml of water [30, 31]. The TW group received 1 ml of water instead of melatonin. Subcutaneous Implant Endodontic sealers (Sealapex, AH Plus and Endofill) were prepared according to the manufacturer’s recommendations and injected in polyethylene tubes (Abbot Labs of Brazil, São Paulo, Brazil) with 1.0-mm internal diameter, 1.6-mm external diameter, and 10.0-mm length (ISO 10993-6: 2007)[32], sterilized in ethylene oxide (ISO 10993-7: 1995)[33]; one tube got empty and it was used as a control. The surgical procedure was performed following previous studies [29]. The rats were anaesthetized and shaved in their dorsal, and a 2.0-cm incision was made in a head-to-tail orientation with a #15 Bard-Parker blade (BD, Franklin Lakes, NJ). The skin was reflected in the extremities, creating two pockets on the right and left side of the incision; Then, the tubes were randomly allocated, and the skin was sutured. A dose of 150mg/Kg of sodium dipyrone was administered and the animals were monitored until they woke up and started feeding themselves. After 5, 15 and 30 days (n = 8 rats/period), the animals were euthanized by an overdose of anaesthetic solution (Figure. 1). The implanted tubes were removed with the surrounding tissue and fixed in 1% formalin solution at a pH of 7.0. The specimens were imbibed in paraffin and sectioned into 5-μm cuts for staining with hematoxylin-eosin, picrosirius red (PSR), immunohistochemistry for IL-6 and TNF-α and 10-μm cuts for staining with von Kossa and not stained for polarized light technique [27, 34]. Histological and immunohistochemical analysis Histological and immunohistochemical analysis were performed by a single calibrated operator in a blinded manner under light microscopy (400x, DM 4000 B: Leica, Wetzlar, Germany). The inflammatory infiltrate was graded in scores from 1 to 4 (1 - no or few inflammatory cells and no reaction; 2 - less than 25 cells and little reaction; 3 - between 25 and 125 cells and moderate reaction; 4 - 125 or more cells and severe reaction). The scores for the immunolabeling of IL-6 and TNF-α were graded also from 1 to 4 (1 - Absence of immunostaining in the region of interest; 2 - Low immunolabeling pattern, about ¼ of labelling of cells and poor labelling in extracellular matrix; 3 - Moderate immunolabeling pattern, about ½ of the immunolabeled cells and moderate labelling in the extracellular matrix; 4 – High immunolabeling pattern, about ¾ of immunolabeled cells and high labelling in the extracellular matrix [35]. The maturation of the collagen was analyzed by the Picrosirius Red staining technique, allowing the identification of greenish-yellow fibres, which were considered immature and thin, and yellowish-red fibres which were considered mature and thick [24]. The LASQWin program was used (400X magnification, Leica LASQWin V3, Leica Microsystems), the variation of colours was selected and automatically the marked area was calculated, indicating the percentage of each kind of fibres observed [29]. The analysis of biomineralization was assessed by the evaluation of calcium deposits in von Kossa staining with deposition of calcium carbonate or in a non-stained technique, the Polarized light, detecting the presence of birefringent crystals [29]. Statistical Analysis Statistical analysis was performed using the SigmaPlot 12.0™ program (Chicago, IL, USA). The normality of the data was verified for all the analyses. The Kruskal-Walli’s test or Mann-Whitney test was performed for nonparametric data. The Tukey post hoc test was performed for parametric data. The level of significance attributed was 5%. Results Inflammatory infiltrate Representative images of the different specimens from all groups are shown in Figure 1. Overall, it was observed a reduction of the inflammatory infiltrate over time. At 5 days, it was observed an intense inflammatory response for all groups, except in the AH Plus and Sealapex groups supplemented with melatonin which was considered moderate. At 15 days, control and Sealapex groups supplemented with melatonin showed a mild inflammatory response, whereas in all other groups was predominantly moderate. At 30 days, mild to absent inflammatory response for the control group and, control and Sealapex groups supplemented with melatonin and moderate to mild inflammatory response in all other groups. In the TW Endofill evoked a more intense inflammatory infiltrate compared to the AH Plus group and control group in the 30 days (p=0.010). There was no difference among all tube responses in any period of analysis (p>0.05) in TM. Comparing each group as a function of the supplementation with melatonin, there are differences for Endofill (p=0.05) and Sealapex (p=0.038) sealer in the 30 days, presenting lower inflammatory infiltrate in the animals that had been treated receiving the melatonin supplementation (Table 1). Inflammatory mediators IL-6 Representative images of the different specimens from all groups about immunolabeling of IL-6 are shown in Figure 2. According to statistics, it can be affirmed that the immunolabeling of IL-6 was lower in the animals that were supplemented with melatonin at 5 (p<0.001); 15 (p=0.005); 30 days (p<0.001) as compared with animals that received water, regardless of the sealer used (Table 2). Comparing the inflammatory response in the TW groups, it can be observed a statistical difference between the control tube and Endofill at 15 days (p0.05). On the other hand, comparing each tube’s response considering the supplementation of melatonin or water, it was observed lower immunolabeling of IL-6 in the control group at 5 (p=0.015) and 15 days (p=0.021), for the AH Plus sealer at 5 (p=0.038), 15 days (p=0.010) and 30 days (p=0.010), and for the Sealapex sealer at 30 days (p=0.010) when the melatonin was used (Table 2). TNF- α Representative images of the different specimens from all groups about immunolabeling of TNF-α are shown in Figure 3. According to statistics, the immunolabeling of TNF-α was lower in the TM groups at 5 (p<0.002), 15 (p<0.001) and 30 days (p=0.004) as compared with animals that received water, regardless of the sealer used (Table 3). In the TW groups, it was observed a static difference between the response of Control and Sealapex (p<0.001), and AH Plus and Sealapex at 30 days (p<0.001). For the TM groups, it was observed a difference between Endofill and AH Plus (p<0.001), and Sealapex and AH Plus at 5 days (p<0.001) and Control and Sealapex at 30 days (p=0.001). Considering each tube’s response according to the supplementation with melatonin or water, it was observed a lower immunolabeling in the AH Plus group at 5 (p=0.038), 15 (p=0.002) and 30 days (p=0.002) when the melatonin was used (Table 3). Collagen Maturity Representative images from Picrosirius red staining to identify the maturity of collagen fibres for all groups are shown in Figure 4. According to Mann-Whitney statistical tests between all groups with melatonin supplementation versus all groups with water supplementation, it can be observed a higher percentage of mature fibres in the groups supplemented with melatonin at 5 days (p=0.024). On the other hand, in the TW groups, the percentage of immature was a higher at 5 days (p=0.024). In the comparative analysis among all TW groups at 5 days, the AH plus group showed more mature fibres compared to Sealapex (p=0.036) and, at 15 days, the Control group showed more mature fibres compared to Endofill (p=0.029). The comparative analysis among all TM groups at 5 days, revealed that control and Endofill tubes had a higher percentage of mature fibres than Sealapex and AH Plus (p0.05). At 30 days there were more mature fibres in the AH Plus and Endofill when compared to the control tube (p=0.005), also with no statistical difference between them. The comparison for each group with supplementation of melatonin or water enable to observe differences in the Control group at 5 days (p<0.001), in the AH Plus group (p=0.011) at 30 days, and in the Endofill group at 5 days (p=0.021), which presented a higher number of mature fibres in the presence of melatonin. On the other hand, the control group, at 15 days, showed higher immature fibres in the presence of melatonin (p=0.015), (Table 4). Calcium deposition Representative images from the Von Kossa staining and birefringent to Polarized light to identify calcium-positive structures for all groups are showed in Figures 5 and 6. For Sealapex endodontic sealer, the presence of calcium deposits in von Kossa staining (Figure 5) and birefringent to polarized light (Figure 6) was observed in all periods of analysis, regardless of supplementation of melatonin. For AH Plus, Endofill, as well as in the control tube, it was not observed any sign of these structures, both in TW groups or TM groups (Table 4) Discussion After being cleaned and shaped, the root canal must be filled with specific materials, the gutta-percha and endodontic sealers [1, 36]. However, these biomaterials when in contact with periapical tissues can induce inflammatory conditions that can even interfere negatively with the periapical repair [4, 8]. Studies suggest that melatonin has an anti-inflammatory ability, with that knowledge, this study evaluated the influence of melatonin supplementation on the tissue response of endodontic sealers. The results showed that melatonin was able to decrease the inflammatory infiltrate and stimulate the repair process and did not inhibit calcium deposition in tissues, which rejects partially our null hypothesis. Melatonin is a hormone produced especially in the pineal gland. Although its main action is to regulate the circadian rhythm [34], this molecule can modulate the inflammatory process, besides regulating the oxidative stress and the proliferation of tumoral cells [15, 16, 24]. These effects are due to its ability to penetrate cells, acting on their DNA and cell structures, such as the plasma membrane [37,38}. A previous study review has shown that melatonin can reduce inflammation in dental clinical conditions [24]. Thus, melatonin may be considered as a potential reducer of the inflammatory process induced by endodontic sealers. Moreover, to enhance the effects of the melatonin in this study, a prophylactic supplementation dose was administered to increase the concentrations of melatonin molecules in the rats, preparing the organism of the experimental animals when getting in contact with the endodontic sealers [39]. The evaluation of tissue responses induced by biomaterials can be observed by implanting standardized polyethylene tubes filled with specific materials into the subcutaneous tissue of rats [29, 32, 33]. The staining of hematoxylin and eosin can show the expression of inflammatory cells indicating the intensity of inflammation [4, 29, 40]. Three different periods of analysis were considered in this project, making it possible to observe a reduction of the inflammatory response of sealers over time, which is referenced in the literature as a natural process promoted by endodontic sealers [4]. However, when was made a comparison between the groups that had the supplementation of melatonin and the group that was supplemented with the vehicle (water), a notable difference was observed, mainly at 30 days, having a lower inflammation in Endoffill and Selapex groups. Endofill is an oxide zinc-based endodontic sealer, whose capacity to induce inflammation is extremely high [8], which could be observed in the TW group, having the Endofill expressing a very intense inflammatory infiltrate. On the other hand, in TM no difference was observed in the inflammatory infiltrate among the different groups of sealers and the control tube, which shows the reduction of the inflammation. In addition, to provide additional evidence about the inflammatory response of the sealers associated with the supplementation of a potential anti-inflammatory substance, the immunolabeling of IL-6 and TNF-α was done [41]. These inflammatory mediators are associated with the regulation of the inflammation, inducing, and modulating it. The IL-6 is produced by several cells, especially by the T-cells and it also can be very easily found in acute responses it has been reported as an interleukin that increases in high levels when tissues are in contact with endodontic sealers [42, 43] For the TNF-α, it is a protein able to recruit inflammatory cells and induce the production of pro and pre inflammatory mediators, being present in every step of the inflammatory process [44]. Consequently, knowing all this information and associating it with its relation to endodontic sealer tissue’s response, the assessment of the immunolabeling of these mediators is considered a particularly important aspect. [43, 45]. According to the findings of the immunohistochemistry analysis, there was an increase of these mediators in the first period of analysis followed by a decrease of them over time, which was expected, since the inflammatory infiltrate is elevated in the beginning, contributing to the proliferation of inflammatory cells, such as lymphocytes and macrophages, which can produce these cytokines [29, 43]. However, when melatonin was supplemented, the immunolabeling of TNF-α and IL-6 was lower even in initial periods. In addition, in the group of sealers that received melatonin, no statistical difference was observed among them for IL-6. The results prove that melatonin has the potential to decrease the inflammatory process by the regulation of the expression of this type of cytokines [24, 42-44]. Still, to investigate even more these associations, more studies must be conducted to understand the interrelation between these pro-inflammatory mediators and the response promoted by endodontic sealers. The type of collagen fibres expressed in the tissues can contribute to the understanding of a biomaterial tissue’s response. It is known that after the inflammation is controlled, there are a proliferation of fibroblasts cells that migrate to the area injured. These cells produce collagen that can be classified in mature, typically found in areas that suffered irritation for longer periods and immature fibres, associated with tissues that are in the beginning of the repair process [46]. The Picrosirus red is a technique that enable to detect the maturity of collagen fibres that are being expressed in the analysed area [29]. After the staining, the detection of mature fibres is seen in a variation of red color and the immature fibres in a variation of green, both in polarized light microscopy [29]. Despite being frequently found in parts that are initializing the repair process, the immature fibres can be also verified in areas going through remodeling process [47]. However, in this study it was observed a higher expression of mature fibres over time in the groups that had the supplementation of melatonin when compared to the groups that were supplemented with water. Therefore, associating to the fact that the melatonin has the ability of decreasing the inflammation in tissues [15,16] and it has the ability of influencing in the deposition of collagen [48]. The association of the results of this experiment and the knowledge provided by the literature, it is possible to say that the expression of more mature fibres was due the maturity of the inflammatory process, which shows tissues renewal indicating its domination by the rat’s immunologic system [15,16]. Although it was possible to evaluate an amelioration of repairment, it is suggested immunohistochemistry analyzes to consolidate the type of collagen in the different periods to understand in which phase the repair would be. Some endodontic sealers, especially those that contain calcium hydroxide in their composition, have the capacity of allowing calcium deposition in tissues, which can be interpreted as the beginning of a mineralization process [40]. These characteristics could also be evaluated in this study by the von Kossa staining, with the expression of calcium carbonate and Polarized light, with the identification of areas with birefringent calcium crystals [29]. Sealapex was the only sealer that had in its composition the calcium hydroxide and the other materials were not based on calcium inducers; thus, as expected, the only sealer that promoted calcification in all periods was Sealapex [40], revealing that melatonin did not interfere in the biomineralization process. These data attest that melatonin was able to modulate the inflammatory process, decreasing the inflammatory infiltrate, the immunolabeling of cytokines, such as TNF-α and IL-6; also, it probably accelerates the remodeling process and do not influence in the biomineralization process. Such remarkable results could be further explored in dentistry, enabling the amelioration of endodontics treatments and the knowledge of clinicians and researchers. Conclusion It can be concluded that melatonin modulated the inflammatory process, decreasing inflammation and the immunolabeling of IL-6 and TNF, stimulating tissue repair and did not influence in calcium deposition. Declarations Author’s Contribution Pedro Henrique Chaves de Oliveira: Responsible for conducting the project, organizing the experiments and laboratories procedures, collection of data, run the statistics, interpreted the results and wrote the manuscript. Michael Júnio da Silva Rodrigues: Responsible for organizing the laboratory experiments, staining of the blades and taking pictures to obtain the results. Cristiane Cantiga da Silva: During all the project helped carrying the animals, organized the experiments, participated in the staining process, helped running the statistics and collaborated in the review of the manuscript. Carolina de Barros Morais Cardoso: Responsible for helping to organize the experiment procedures, collect the data e review the manuscript. Flávio Duarte Faria: Responsible for helping to organize the experiment procedures, collect the data e review the manuscript. Leopoldo Cosme da Silva: Responsible to execute the surgical procedure, to organize the results obtained and in the review of the manuscript. Edilson Ervolino: Responsible for conducting the immunohistochemistry staining, contributed to the comprehension of the results obtained, especially for the inflammatory mediators and maturity of collagen and reviewed the manuscript as well. Luciano Tavares Angelo Cintra: Responsible for supervising all the experiment, laboratory procedures, data collection, manuscript writing, reviewed the statistics and helped in the understanding of the results obtained. Ethics Approval and Consent Ethical Principals of Animal Experimentation and its implantation was approved by CEUA - (Protocol FOA no. 00433-2018), São Paulo State University (Unesp), Araçatuba, SP, Brazil. The study was with animals, for that reason the only consent needed was from the local ethical committee Funding Fundação de Amparo à Pesquisa do Estado de São Paulo (Process no. 2017/24713-7) Conflict of interest The authors deny any conflicts of interest related to this study. References Ørstavik D (2014) Endodontic filling materials. Endod Top 31:53– 67. Guttuso J (1963) Histopathologic study of rat connective tissue responses to endodontic materials. Oral Surg Oral Med Oral Pathol 6:713-27. Morse DR, Martell B, Pike CG, Fantasia J, Esposito JV, Furst ML (1984) A comparative tissue toxicity evaluation of Gutta-percha root canal sealers. Part II. Forty-eight-hour findings. J Endod 10:484-6. Benetti F, Queiroz IOA, Oliveira PHC, Conti LC, Azuma MM, Oliveira SHP, Cintra LTA (2019) Cytotoxicity and biocompatibility of a new bioceramic endodontic sealer containg calcium hydroxide. Brazilian of Oral Research 33; e42 Geurtsen W (2001). Biocompatibility of root canal filling materials. Aust Endod J 27(1):12-21. doi: 10.1111/j.1747-4477.2001.tb00445.x. PMID: 11481874. Kim YK, Grandini S, Ames JM, Gu LS, Kim SK, Pashley DH et al (2010) Critical review on methacrylate resin-based root canal sealers. J Endod 36(3):383-99. Silva Almeida LH, Moraes RR, Morgental RD, Pappen FG (2017) Are Premixed Calcium Silicate-based Endodontic Sealers Comparable to Conventional Materials? A Systematic Review of In Vitro Studies. J Endod 43(4):527-535. doi: 10.1016/j.joen.2016.11.019. Epub 2017 Feb 16. PMID: 28216270. Zmener O, Lalis RM, Pameijer CH, Chaves C, Kokubu G, Grana D (2012) Reaction of rat subcutaneous connective tissue to a mineral trioxide aggregate-based and a zinc oxide and eugenol sealer. J Endodontics 38:1233-1238. Slominski R M, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT (2012) Melatonin membrane receptors in peripheral tissues, distribution and functions. Molecular and Cellular Endocrinology 351:152-166. Azuma MM, Gomes-Fiho JE, Ervolino E, Pipa CB, Cardoso CBM, Andrada AC, Kawai T, Cintra LTA (2017) Omega 3 fatty acids reduce boné resorption while promoting boné generation in rat apical periodontitis. J Endod 43:970-76. Noori-Hassanvan M, Soleimani Mehranjani M, Shojafar E (2017) Melatonin improves the structure and function of autografted mice ovaries through reducing inflammation: A stereologican and biochemical analysis. International Immunopharmacology 74:105679. Reiter RJ, Tan DX, Korkmaz A (2009) The circadian melatonin rhythm and its modulation: possible impact on hypertension. Journal of Hypertension Supplement 27;S17-S20. Singh M, Jadhav HR (2014) Melatonin: functions and ligands. Drug Discovery Today 19:1410–1418. Acuña-Castroviejo D, Escames G, Venegas C et al. (2014) Extrapineal melatonin: sources, regulation, and potential functions. Cellular and Molecular Life Sciences 71:2997–3025. Mauriz JL, Collado PS, Vaneroso C, Reiter RJ, Gonzáles-Gallego J (2013) A review of the molecular aspectes of melatonin’s anti-inflamatory actions: recent insights and new perspectives. Journal of Pineal Research 54:1-14. Dong Y, Fan C, Hu W, et al (2016) Melatonin attenuated early brain injury induces by sbarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling. Journal of Pineal Research. 60:253-262. Colares JR, Schemitt EG, Hartmann RM, Licks F, Soares MD, Bosco AD, Marroni NP (2016) Antioxidant and anti-inflammatory action of melatonin in an experimental model of secondary biliary cirrhosis induced by bile duct ligation. World J. Gastroenterol 22:8918-8928. Ostjen CA, Rosa CGS, Hartmann RM, Schemitt EG, Colares JR, Marroni NP (2019) Anti-inflammatory and antioxidant effect of melatonin on recovery from muscular trauma induced in rats. Exp Mol Pathol. 106:52-59. Baeuerle PA, Baltimore D (1996) NF-Kappa B: ten years after. Cell 87:13-20. Reiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX(2000) Melatonin and its relation to the immune system and inflammation. Ann N Y Acad Sci 917:376-86. Cuzzocrea S, Reiter RJ (2001) Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury. Eur J Pharmacol 24;426(1-2):1-10. Vriend J, Reiter RJ (2014) Melatonin as a proteasome inhibitor. Is there any clinical evidence? Life Sciences 115:8-14. Favero G, Franseschetti L, Bonomini F, Rodella LF, Rezzani.R (2017) Melatonin as Anti-Inflamatory angent modulating inflammasome activation. Int J Endocrinol 2017:1835-195. de Oliveira PHC, Lemos CAA, Cantiga-Silva C, Faria FD, Cintra LTA, Pellizzer EP (2021) Melatonin as an adjunctive treatment on dental procedures: A systematic review. Oral Dis. 28 :1770–1782. doi: 10.1111/odi.13941. León J, Casado J, Jiménez Ruiz SM, et al (2014) Melatonin reduces endothelin-1 expression and secretion in colon cancer cells through the inactivation of FoxO-1 and NF-κβ. J Pineal Res . 56:415-426. doi:10.1111/jpi.12131 Habtemariam S, Daglia M, Sureda A, Selamoglu Z, Gulhan MF, Nabavi SM (2017) Melatonin and respiratory diseases: a review. Current Topics in Medicinal Chemistry 17:467-488. de Oliveira PHC, Gomes Filho JE, Rodrigues MJDS, da Silva CC, Cardoso CDBM, Cosme daSilva L, Ervolino E, Cintra LTA (2022) Influence of supplement administration of omega-3 on the subcutaneous tissue response of endodontic sealers in Wistar rats. Int Endod J. 55:1026-1041. doi: 10.1111/iej.13795. Epub 2022 Jul 16. PMID: 35791796. Nagendrababu V, Kishen A, Murray PE, et al (2021) PRIASE 2021 guidelines for reporting animal studies in Endodontology: a consensus-based development. Int Endod J . 54:848-857. Cintra LTA, Benetti F, de Azevedo Queiroz ÍO, de Araújo Lopes JM, Penha de Oliveira SH, Sivieri Araújo G, Gomes-Filho JE (2017a) Cytotoxicity, Biocompatibility, and Biomineralization of the New High-plasticity MTA Material. J Endod 43:774-778. Santos M, Favero G, Bonomini F, Stacchiotti A, Rodella LF, Veronese FV, Rezzani R (2017) Oral supplementation of melatonin protects against lupus nephritis renal injury in a pristane-induced lupus mouse model. Life Sciences 193:242-251 Li JG, Lin JJ, Wang ZL, Cai WK, Wang PN, Jia Q, Zhang AS, Wu GY, Zhu GX, Ni LX. (2015) Melatonin attenuates inflammation of acute pulpitis subjected to dental pulp injury. Am J Transl Res 7;166-78. ISO 10993-6. Biological evaluation of medical devices. Part 6: Tests for local effects nafter implantation International Standard Norm, Porto, Portugal (2007). ISO 10993-7. Biological evaluation of medical devices. Part 7: Ethylene oxide sterilization residuals. International Standard Norm, Porto, Portugal (2008). Gomes-Filho JE, Duarte PC, de Oliveira CB, Watanabe S, Lodi CS, Cintra LT, Bernabé PF (2012) Tissue reaction to a triantibiotic paste used for endodontic tissue self-regeneration of nonvital immature permanent teeth. J Endod 38:91-4. Benetti F, Briso ALF, Ferreira LL, Carminatti M, Alamo L, Ervolino E, Dezan-Júnior E, Cintra LTA (2018) In Vivo Study of the Action of a Topical Anti-Inflammatory Drug In Rat Teeth Submitted To Dental Bleaching. Braz. Dent. J 29;555-561. Sadr S, Golmoradizadeh A, Raoof M, Tabanfar MJ (2015) Microleakage of Single-Cone Gutta-Percha Obturation Technique in Combination with Different Types of Sealers. Iran Endod J 10(3):199-203. Tan DX, Reiter RJ, Chen LD, Poggeler B, Poeggeler B, Manchester LC, Barlow-Walden LR (2011) Pharmacological levels of melatonin reduce DNA adduct formation. Both Physiological and Mol Cell Biochem 353:139–149. Melchiorii D, Reiter RJ, Attia A, Hara M, Burgos A, Nistico G (1995) Potent protective effect melatonin on in vivo paraquat induced toxicity. Life Sci 56:83–88 Renn TY, Huang YK, Feng SW, Wang HW, Lee WF, Lin CT, Burnouf T, Chen LY, Kao PF, Chang HM (2018) Prophylactic supplement with melatonin successfully suppres the pathogenesis of periodontitis though mormalizing RANKL/OPG ratio and depressing the TLR4/MyD88 signaling pathway. J. Pineal Res 64:e12464 Bueno CR, Valentim D, Marques VAS., Gomes-Filho JE, Cintra LTA, Jacinto RC, Dezan-Junio E (2016) Biocompatibility and biomineralizantion assessment of bioceramic, epoxy, and calcium hydroxide-based sealers. Braz. Oral Res 30:1-9. Nibali L, Fedele S, D'Aiuto F, Donos N (2012) Interleukin-6 in oral diseases: a review. Oral Dis 8: 236-43. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newer G, Schaper F (2003) Principles of interleukin (IL-6) type cytokine signaling and its regulation. Biochemical J 374:1-20. Silva GF, Tanomaru-Filho M, Bernardi MI, et al (2015) Niobium pentoxide as radiopacifying agent calcium silicate-based material: evaluation of physicochemical and biological properties. Clin Oral Investig 19:2012–25 Pfeffer K (2003) Biological functions of tumor necrosis factor cytokines and their receptors. Cytok Growth Fact Rev 14:185-91 Chang et al 2015 Diegelmann RF, Evans MC (2004) Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci 9:283-9. Zerbinati N, Calligaro A (2018) Calcium hydroxylapatite treatment of human skin: evidence of collagen turnover through picrosirus red staining and circularly polarized microscopy. Clin Cosmet Investig Dermatol 11:29-35. Bona S, Rodrigues G, Moreira AJ, Di Naso FC, Dias AS, Da Silveira TR, Marroni CA, Marroni NP (2018) Antifibrogenic effect of melatonin in rats with experimental liver cirrhosis induced by carbon tetrachloride. JGH Open. 2:117-123. doi: 10.1002/jgh3.12055. PMID: 30483575; PMCID: PMC6206983. Tables Table 1. Scores observed for inflammatory response of endodontic sealers and oral supplementation of Melatonin Period of analysis Score H.E. Staining for Groups Control Control + Melatonin AH Plus AH Plus + Melatonin Endofill Endofill + Melatonin Sealapex Sealapex+ Melatonin Statistical Analysis 5 days 1 0/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 2 2/8 2/8 1/8 3/8 1/8 0/8 2/8 1/8 3 3/8 3/8 3/8 3/8 3/8 4/8 3/8 4/8 p<0.001 4 3/8 3/8 4/8 2/8 4/8 4/8 3/8 3/8 Median** 3,5 Aa 3,5 Aa 4 Aa 2,5 Ba 4 Aa 3,5 Aa 3,5 Aa 3 Ba 15 days 1 1/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 2 1/8 4/8 2/8 3/8 1/8 2/8 2/8 4/8 3 4/8 2/8 5/8 4/8 4/8 2/8 6/8 2/8 p=0.005 4 2/8 2/8 1/8 1/8 3/8 4/8 0/8 2/8 Median** 3 Aa 2 Aa 3 Aa 3 Aa 3 Aa 4 Aa 3 Aa 2,5 Aa 30 days 1 3/8 3/8 2/8 2/8 0 /8 1/8 0/8 4/8 2 3/8 4/8 3/8 3/8 1/8 5/8 4/8 3/8 3 2/8 1/8 3/8 3/8 5/8 1/8 4/8 1/8 p<0.001 4 0/8 0/8 0/8 0/8 2/8 1/8 0/8 0/8 Median** 1,5 Ac 2 Aa 2,5 Aa 2,5 a 3 Aa 2 Bb 2,5 Aab 1 Bab ** Superscript uppercase for analysis into different sealers supplemented with water or into different sealers supplemented with melatonin. Supperscript lower case letters for two groups analysis (Control versus Control + Melatonin; AH Plus versus AH Plus + Melatonin; Endofill versus Endofill + Melatonin; Sealapex versus Sealapex + Melatonin) Table 2. Scores observed for the expression of IL-6 by endodontic sealers with and without the supplementation of melatonin. Period of analysis Score IL-6. Staining for Groups Control Control + Melatonin AH Plus AH Plus + Melatonin Endofill Endofill + Melatonin Sealapex Sealapex+ Melatonin Statistical Analysis 5 days 1 0/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 2 0/8 2/8 0/8 5/8 0/8 0/8 0/8 2/8 3 3/8 6/8 3//8 1/8 3/8 6/8 8/8 6/8 p<0.001 4 5/8 0/8 5/8 2/8 5/8 2/8 0/8 0/8 Median** 4 Aa 3 Ba 4 Aa 2 Ba 4 Aa 3 Ba 3 Aa 3 Ba 15 days 1 0/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 2 0/8 1/8 0/8 6/8 3/8 2/8 0/8 1/8 3 3/8 7/8 8/8 2/8 5/8 6/8 8/8 7/8 p=0.005 4 5/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 Median** 4 Aab 3 Ba 3 Aa 2 Ba 3 Ac 3 Ba 3 Aa 3 Ba 30 days 1 0/8 0/8 0/8 0/8 0 /8 0/8 0/8 0/8 2 0/8 0/8 0/8 6/8 3/8 6/8 0/8 6/8 3 5/8 8/8 8/8 2/8 5/8 2/8 8/8 2/8 p<0.001 4 3/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 Median** 3 Aa 3 Ba 3 Aa 2 Ba 3 Aa 2 Ba 3 Aa 2 Ba ** Superscript uppercase for analysis into different sealers supplemented with water or into different sealers supplemented with melatonin. Supperscript lower case letters for two groups analysis (Control versus Control + Melatonin; AH Plus versus AH Plus + Melatonin; Endofill versus Endofill + Melatonin; Sealapex versus Sealapex + Melatonin) Table 3. Scores observed for the immunolabeling of TNF-α by endodontic sealers with and without the supplementation of melatonin. Period of analysis Score TNF-α Staining for Groups Control Control + Melatonin AH Plus AH Plus + Melatonin Endofill Endofill + Melatonin Sealapex Sealapex+ Melatonin Statistical Analysis 5 days 1 0/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 2 0/8 2/8 0/8 7/8 0/8 0/8 /8 0/8 3 5/8 6/8 6/8 1/8 5/8 8/8 8/8 8/8 p<0.002 4 3/8 0/8 2/8 0/8 3/8 0/8 0/8 3/8 Median** 3,5 B 3,5 Aa 3 B 2 Abc 3 Bb 3 Ac 3 B 3 Ab 15 days 1 0/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 2 0/8 2/8 0/8 7/8 0/8 2/8 0/8 2/8 3 5/8 6/8 8/8 1/8 8/8 6/8 8/8 6/8 p=0.001 4 3/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 Median** 3 B 3 Ab 3 B 2 Ab 3 B 3 Aa 3 B 2 Aa 30 days 1 0/8 0/8 0/8 0/8 0 /8 0/8 0/8 0/8 2 0/8 1/8 0/8 7/8 2/8 5/8 8/8 8/8 3 5/8 7/8 8/8 1/8 6/8 3/8 0/8 0/8 P=0.004 4 3/8 0/8 0/8 0/8 0/8 0/8 0/8 0/8 Median** 3 B 3 Aa 2 Bac 2 Aab 3 Babc 2 Aab 2 Bb 2 Ab ** Superscript uppercase for analysis into different sealers supplemented with water or into different sealers supplemented with melatonin. Supperscript lower case letters for two groups analysis (Control versus Control + Melatonin; AH Plus versus AH Plus + Melatonin; Endofill versus Endofill + Melatonin; Sealapex versus Sealapex + Melatonin) Table 4. Median of mature and immature fibers and mineralization capacity for each sealer in both experimental groups (Results on %) Groups Time Material Collagen Maturity (%) Mineralization (%) Mature Fibers Imature Fibers VK POL Control 05 days Control 52.697 a 47.303 0 0 AH Plus 66.158 A 33.842 0 0 Endofill 61.065 a 38.935 0 0 Sealapex 39.223 B 60.777 100 100 15 days Control 65.508 A 34.492 a 0 0 AH Plus 64.982 35.018 0 0 Endofill 47.279 B 52.721 0 0 Sealapex 51.587 48.413 100 100 30 days Control 69.665 30.335 0 0 AH Plus 56.260 a 43.740 0 0 Endofill 61.686 38.314 0 0 Sealapex 78.405 21.595 100 100 Melatonin 05 days Control 80.029 Ab 19.971 0 0 AH Plus 55.311 B 44.681 0 0 Endofill 81.923 Ab 18.077 0 0 Sealapex 50.441 B 49.559 100 100 15 days Control 52.810 47.190 b 0 0 AH Plus 59.995 40.005 0 0 Endofill 45.185 54.815 0 0 Sealapex 55.357 44.643 100 100 30 days Control 48.862 A 51.138 0 0 AH Plus 84.011 Bb 15.989 0 0 Endofill 74.249 B 25.751 0 0 Sealapex 66.823 33.177 100 100 * Superscript capital letters represent statistical diferences among the melatonin supplemented groups or water supplemented groups in each period (analysis among 4 groups) * Superscript lowercase letters for two groups in each period of analysis by Mature and Imature Fibers (Control versus Control + melatonin; AH Plus versus AH Plus + melatonin; Endofill versus Endofill + melatonin; Sealapex versus Sealapex + melatonin) Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3649915","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":254187844,"identity":"45e71161-89ec-4395-be29-af25d5786a36","order_by":0,"name":"Pedro Henrique Chaves de Oliveira","email":"","orcid":"","institution":"Department of Preventive and Restorative Dentistry, São Paulo State University (Unesp), School of Dentistry, Araçatuba, SP","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pedro","middleName":"Henrique Chaves","lastName":"de Oliveira","suffix":""},{"id":254187845,"identity":"e6477ba1-2b0a-42dd-a33e-707254a141a8","order_by":1,"name":"Michael Júnio da Silva Rodrigues","email":"","orcid":"","institution":"Department of Preventive and Restorative Dentistry, São Paulo State University (Unesp), School of Dentistry, Araçatuba, SP","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"Júnio da Silva","lastName":"Rodrigues","suffix":""},{"id":254187846,"identity":"a9ffcf9d-f936-4253-bd18-ce217279f0ac","order_by":2,"name":"Cristiane Cantiga da Silva","email":"","orcid":"","institution":"Department of Preventive and Restorative Dentistry, São Paulo State University (Unesp), School of Dentistry, Araçatuba, SP","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Cristiane","middleName":"Cantiga da","lastName":"Silva","suffix":""},{"id":254187847,"identity":"cf92efab-3e59-468a-bef7-ef7b3dbfb182","order_by":3,"name":"Carolina de Barros Morais Cardoso","email":"","orcid":"","institution":"Department of Preventive and Restorative Dentistry, São Paulo State University (Unesp), School of Dentistry, Araçatuba, SP","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Carolina","middleName":"de Barros Morais","lastName":"Cardoso","suffix":""},{"id":254187848,"identity":"3c99a2d9-47c1-4851-9cba-eaa386f1d77c","order_by":4,"name":"Flávio Duarte Faria","email":"","orcid":"","institution":"Department of Preventive and Restorative Dentistry, São Paulo State University (Unesp), School of Dentistry, Araçatuba, SP","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Flávio","middleName":"Duarte","lastName":"Faria","suffix":""},{"id":254187849,"identity":"dc0d2f64-6266-4772-980f-f41ca781a8f1","order_by":5,"name":"Leopoldo Cosme da Silva","email":"","orcid":"","institution":"Department of Endodontics, School of Dentistry, Alagoas Federal University (UFAL), Maceió, AL, Brazil","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Leopoldo","middleName":"Cosme da","lastName":"Silva","suffix":""},{"id":254187850,"identity":"57e30d6d-7320-481e-aa9d-124a8e3a7c08","order_by":6,"name":"Edilson Ervolino","email":"","orcid":"","institution":"Department of Basic Science, São Paulo State University (Unesp), Araçatuba, SP","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Edilson","middleName":"","lastName":"Ervolino","suffix":""},{"id":254187851,"identity":"69a95171-d8cb-4b80-b652-9f126f49f561","order_by":7,"name":"Luciano Tavares Angelo Cintra","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6UlEQVRIiWNgGAWjYBACPiA+AGYxg0kbiDBjA24tbEhaQOrSiNMCAyB1h4nQIpH88MDPHTYM/O28xx9X1JxP3M7e/uwB4457eLSkGRzsPZPGIHGYL7HxzLHbiTt7zpgbMJ4pxqMlh+EAb9thBgNmHsPGBrbbiRtu5LBJMLYl4NVy8C9cy79ziRvuP39GUMthuC2NbQeAtjCY4dfC88zgsGxbGo/EYR7DmY19ycYbzuSYGySewa2Fnz358ce3bTZy/P1nDD42fLOT3XD8+LMHH3fg1gIDPChWMxDWgO5aUjWMglEwCkbB8AYAh/5TriYKlvMAAAAASUVORK5CYII=","orcid":"","institution":"Department of Preventive and Restorative Dentistry, São Paulo State University (Unesp), School of Dentistry, Araçatuba, SP","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Luciano","middleName":"Tavares Angelo","lastName":"Cintra","suffix":""}],"badges":[],"createdAt":"2023-11-22 16:59:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3649915/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3649915/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":47465638,"identity":"57f12ff5-aee6-4374-b38a-9597adc72049","added_by":"auto","created_at":"2023-12-02 00:55:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1016079,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative images from the subcutaneous tissue reactions for groups with water supplementation (A-D. E-H; I-L) and groups with melatonin supplementation (a-d. e-h, i-l) for each kind of sealer and the control tube used at 5, 15 and 30 days of analysis (A,a; E,e. I, I – Control; B,b; F,f;J,j – AH Plus; C,c; G,g;K,k – Endofill and D,d, H,h;L,l – Sealapex). (Hematoxylin-eosin staining, x400).\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3649915/v1/39b3a8add526296075e895e3.png"},{"id":47465637,"identity":"4b185d99-f08d-46d4-a63d-2285a63f3d0b","added_by":"auto","created_at":"2023-12-02 00:55:47","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1077807,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemistry images of in situ IL-6 expression for groups supplemented with water (A-D, E-H, I-L) and with melatonin (a-d, e-h, i-l) for control tube (A,a; E,e; I,I), AH Plus (B,b; F,f; J,j), Endofill (C,c; G,g; K,k) and Sealapex (D,d, H,h; L,l) at 5 days (A-D, a-d), 15 days (E-H, e-h) and 30 days (I-L, i-l) of analysis. (Immunolabeling for IL-6, x400).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3649915/v1/62bb085a089ac1673f2bc584.png"},{"id":47465639,"identity":"add2f37f-a6d6-4833-8d66-240bb293c78f","added_by":"auto","created_at":"2023-12-02 00:55:47","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1127119,"visible":true,"origin":"","legend":"\u003cp\u003eImmunohistochemistry images of in situ TNF-α expression for groups supplemented with water (A-D, E-H, I-L) and with melatonin (a-d, e-h, i-l) for control tube (A,a; E,e; I,I), AH Plus (B,b; F,f; J,j), Endofill (C,c; G,g; K,k) and Sealapex (D,d, H,h; L,l) at 5 days (A-D, a-d), 15 days (E-H, e-h) and 30 days (I-L, i-l) of analysis. (Immunolabeling for IL-6, x400).\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3649915/v1/e320d2488a2043fe9914ba01.png"},{"id":47466299,"identity":"e3157f7d-d99e-4bcf-bb09-39674d252c32","added_by":"auto","created_at":"2023-12-02 01:11:47","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":908974,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative images from the Picrosirius red staining to identify the maturity of the collagen fibres for groups supplemented with water (A-D, E-H, I-L) and with melatonin. (a-d, e-h, i-l) for control tube (A,a; E,e; I,I), AH Plus (B,b; F,f; J,j), Endofill (C,c; G,g; K,k) and Sealapex (D,d, H,h; L,l) at 5 days (A-D, a-d), 15 days (E-H, e-h) and 30 days (I-L, i-l) of analysis. (PSR staining, x100).\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3649915/v1/512ee8cf47bc1d1eb3655a5b.png"},{"id":47465928,"identity":"cfd3b42f-9503-47ee-b885-33b0e038c7d5","added_by":"auto","created_at":"2023-12-02 01:03:47","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":930073,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative images from Von Kossa staining for groups supplemented with water (A-D, E-H, I-L) and with melatonin (a-d, e-h, i-l) for control tube (A,a; E,e; I,I), AH Plus (B,b; F,f; J,j), Endofill (C,c; G,g; K,k) and Sealapex (D,d, H,h; L,l) at 5 days (A-D, a-d), 15 days (E-H, e-h) and 30 days (I-L, i-l) of analysis. Structures positive for von Kossa staining can be seen in the tissue reaction induced by Sealapex at 5, 15 and 30 days regardless of supplementation of melatonin (D,d; H,h; L,l). (Staining according to the von Kossa technique, x100).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-3649915/v1/43131b8cd0208a6e586fdfdf.png"},{"id":47465634,"identity":"8fa0bc44-4b19-40f7-8e29-790800cbda2b","added_by":"auto","created_at":"2023-12-02 00:55:47","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":235154,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative images from Polarized light for groups supplemented with water (A-D, E-H, I-L) and with omega 3 (a-d, e-h, i-l) for control tube (A,a; E,e; I,I), AH Plus (B,b; F,f; J,j), Endofill (C,c; G,g; K,k) and Sealapex (D,d, H,h; L,l) at 5 days (A-D, a-d), 15 days (E-H, e-h) and 30 days (I-L, i-l) of analysis. The birefringent calcium crystals can be seen in the tissue reaction induced by Sealapex at 5, 15 and 30 days regardless of supplementation with melatonin. (D,d; H,h; L,l). (Polarized light visualization, x100x).\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-3649915/v1/be2c70d04900c35fc72db4b0.png"},{"id":48322890,"identity":"440e5444-0dde-44f9-bf89-ab4dc12446d5","added_by":"auto","created_at":"2023-12-16 14:52:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5340184,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3649915/v1/b09bd9d0-04e2-4b38-b6b9-08fe649448b1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Influence of melatonin supplementation on tissue response of endodontic sealers in Wistar rats","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe filling of the root canals is done by using endodontic sealers that along with the gutta percha allow the canal obturation [1]. In this context, an ideal endodontic sealer must present specific biological and physicochemical characteristics, such as biocompatibility and dimensional stability\u0026nbsp;[2,3]. Different responses can be observed in tissues, depending on the sealer base compound [2-4]. Consequently, these reactions can influence periapical repair, inducing or even delaying it [5,6]. The ones based on oxide zinc, for example, can promote a more exacerbated inflammatory response, while others that contain different formulations induce lower inflammation, such as those based on calcium silicate, which also can induce the mineralization process [4,7,8].\u003c/p\u003e\n\u003cp\u003eThe local inflammatory response can be modulated by different substances [9-11], one of them is melatonin (N-acetil-5-metoxitriptamine), an endogenous indolamine, produced in the absence of light by the pineal gland and other areas of the body, such as the retina, salivary gland and even inflammatory cells [12-14]. This indolamine performs different functions, such as chronobiological, immunomodulatory, sedative, antitumor, analgesic, anti-inflammatory and antioxidant functions [15-18].\u003c/p\u003e\n\u003cp\u003eAs an anti-inflammatory agent, several studies have demonstrated that melatonin can regulate the inflammatory process ceasing innumerable events within the cell cascade by the signalling of NF-k\u003cem\u003e\u0026beta;\u003c/em\u003e (Nuclear transcription factor \u0026ndash; Kappa \u003cem\u003e\u0026beta;)\u003c/em\u003e, which is translocated to the nucleus of cells, binding itself to specific elements that modulate the transcription of pro-inflammatory genes [19-24]. In addition, melatonin can influence the expression of pro-inflammatory and anti-inflammatory cytokines, and the recruitment of polymorphonuclear leukocytes to sites of inflammation in different pathophysiological situations [25, 26]. Besides, this substance is proven to be a regulator of inflammation in dental conditions, such as periodontitis diseases, mucositis and it can potentiate the repair process in teeth extractions, implants and periodontal areas [24].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsidering that endodontic sealers can develop local inflammatory reactions on connective tissues and that melatonin is a potential regulator of the inflammatory process, the present study evaluated the influence of melatonin supplementation on tissue\u0026rsquo;s response to endodontic sealers by a consolidated method of exploring the biomaterials response, the implantation of polyethylene tubes in subcutaneous tissues of Wistar rats [27]. Null hypothesis: Melatonin would not interfere with the tissue\u0026rsquo;s response to endodontic sealers.\u0026nbsp;\u003c/p\u003e"},{"header":"Material And Methods","content":"\u003cp\u003eThe manuscript of this animal study has been written according to Preferred Reporting Items for Animal studies in Endodontology (PRIASE) 2021 guidelines [28].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExperimental Animals\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFollowing the protocols of previous studies, using an alpha error of 0.05% and 95% power to recognize a significant difference of 1 in the median scores, a minimum of seven animals per group was considered necessary. Taking into consideration the possible complications that could occur during the study, one more animal was added to each group (TM and TW) in each experimental time. Considering three observation times, 48 animals were necessary in this study [4, 27, 29], They were caged in a controlled temperature and light cycle environment (22 \u0026plusmn; 1 \u0026deg; C, 70% humidity at 12 hours light and 12 hours dark), received solid diet and ad libitum water, except for the first 24 hours after the intervention. The experimental procedures were approved and performed according to the guidelines of the ethical committee (process no. 00433-2018).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMelatonin supplementation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHalf of the animals were supplemented with melatonin (Group treated with melatonin \u0026ndash; TM) and the other half with water (Group treated with water \u0026ndash; TW). \u0026nbsp;The supplementation occurred 15 days before the implantation of the endodontic sealers and lasted until the sacrifice day, as a therapy supplementation. The dose of melatonin was 10mg/kg/day dissolved in 1 % ethanol and 1 ml of water [30, 31]. The TW group received 1 ml of water instead of melatonin.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubcutaneous Implant\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEndodontic sealers (Sealapex, AH Plus and Endofill) were prepared according to the manufacturer\u0026rsquo;s recommendations and injected in polyethylene tubes (Abbot Labs of Brazil, S\u0026atilde;o Paulo, Brazil) with 1.0-mm internal diameter, 1.6-mm external diameter, and 10.0-mm length (ISO 10993-6: 2007)[32], sterilized in ethylene oxide (ISO 10993-7: 1995)[33]; one tube got empty and it was used as a control. The surgical procedure was performed following previous studies [29]. The rats were anaesthetized and shaved in their dorsal, and a 2.0-cm incision was made in a head-to-tail orientation with a #15 Bard-Parker blade (BD, Franklin Lakes, NJ). The skin was reflected in the extremities, creating two pockets on the right and left side of the incision; Then, the tubes were randomly allocated, and the skin was sutured. A dose of 150mg/Kg of sodium dipyrone was administered and the animals were monitored until they woke up and started feeding themselves.\u003c/p\u003e\n\u003cp\u003eAfter 5, 15 and 30 days (n = 8 rats/period), the animals were euthanized by an overdose of anaesthetic solution (Figure. 1). The implanted tubes were removed with the surrounding tissue and fixed in 1% formalin solution at a pH of 7.0. The specimens were imbibed in paraffin and sectioned into 5-\u0026mu;m cuts for staining with hematoxylin-eosin, picrosirius red (PSR), immunohistochemistry for IL-6 and TNF-\u0026alpha; and 10-\u0026mu;m cuts for staining with von Kossa and not stained for polarized light technique [27, 34].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHistological and immunohistochemical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHistological and immunohistochemical analysis were performed by a single calibrated operator in a blinded manner under light microscopy (400x, DM 4000 B: Leica, Wetzlar, Germany). The inflammatory infiltrate was graded in scores from 1 to 4 (1 - no or few inflammatory cells and no reaction; 2 - less than 25 cells and little reaction; 3 - between 25 and 125 cells and moderate reaction; 4 - 125 or more cells and severe reaction). The scores for the immunolabeling of IL-6 and TNF-\u0026alpha; were graded also from 1 to 4 (1 - Absence of immunostaining in the region of interest; 2 - Low immunolabeling pattern, about \u0026frac14; of labelling of cells and poor labelling in extracellular matrix; 3 - Moderate immunolabeling pattern, about \u0026frac12; of the immunolabeled cells and moderate labelling in the extracellular matrix; 4 \u0026ndash; High immunolabeling pattern, about \u0026frac34; of immunolabeled cells and high labelling in the extracellular matrix [35].\u003c/p\u003e\n\u003cp\u003eThe maturation of the collagen was analyzed by the Picrosirius Red staining technique, allowing the identification of greenish-yellow fibres, which were considered immature and thin, and yellowish-red fibres which were considered mature and thick [24]. The LASQWin program was used (400X magnification, Leica LASQWin V3, Leica Microsystems), the variation of colours was selected and automatically the marked area was calculated, indicating the percentage of each kind of fibres observed [29]. The analysis of biomineralization was assessed by the evaluation of calcium deposits in von Kossa staining with deposition of calcium carbonate or in a non-stained technique, the Polarized light, detecting the presence of birefringent crystals [29].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analysis was performed using the SigmaPlot 12.0\u0026trade; program (Chicago, IL, USA). The normality of the data was verified for all the analyses. The Kruskal-Walli\u0026rsquo;s test or Mann-Whitney test was performed for nonparametric data. The Tukey post hoc test was performed for parametric data. The level of significance attributed was 5%.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eInflammatory infiltrate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRepresentative images of the different specimens from all groups are shown in Figure 1. Overall, it was observed a reduction of the inflammatory infiltrate over time. At 5 days, it was observed an intense inflammatory response for all groups, except in the AH Plus and Sealapex groups supplemented with melatonin which was considered moderate. At 15 days, control and Sealapex groups supplemented with melatonin showed a mild inflammatory response, whereas in all other groups was predominantly moderate. At 30 days, mild to absent inflammatory response for the control group and, control and Sealapex groups supplemented with melatonin and moderate to mild inflammatory response in all other groups. In the TW Endofill evoked a more intense inflammatory infiltrate compared to the AH Plus group and control group in the 30 days (p=0.010). There was no difference among all tube responses in any period of analysis (p\u0026gt;0.05) in TM. Comparing each group as a function of the supplementation with melatonin, there are differences for Endofill (p=0.05) and Sealapex (p=0.038) sealer in the 30 days, presenting lower inflammatory infiltrate in the animals that had been treated receiving the melatonin supplementation (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInflammatory\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003emediators\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIL-6\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRepresentative images of the different specimens from all groups about immunolabeling of IL-6 are shown in Figure 2. According to statistics, it can be affirmed that the immunolabeling of IL-6 was lower in the animals that were supplemented with melatonin at 5 (p\u0026lt;0.001); 15 (p=0.005); 30 days (p\u0026lt;0.001) as compared with animals that received water, regardless of the sealer used (Table 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eComparing the inflammatory response in the TW groups, it can be observed a statistical difference between the control tube and Endofill at 15 days (p\u0026lt;0.001), with more immunolabeling for Endofill of the inflammatory mediator. No statistical difference was observed among the TM groups in any period (p\u0026gt;0.05). On the other hand, comparing each tube\u0026rsquo;s response considering the supplementation of melatonin or water, it was observed lower immunolabeling of IL-6 in the control group at 5 (p=0.015) and 15 days (p=0.021), for the AH Plus sealer at 5 (p=0.038), 15 days (p=0.010) and 30 days (p=0.010), and for the Sealapex sealer at 30 days (p=0.010) when the melatonin was used (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTNF-\u0026nbsp;\u0026alpha;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRepresentative images of the different specimens from all groups about immunolabeling of TNF-\u0026alpha; are shown in Figure 3. According to statistics, the immunolabeling of TNF-\u0026alpha; was lower in the TM groups at 5 (p\u0026lt;0.002), 15 (p\u0026lt;0.001) and 30 days (p=0.004) as compared with animals that received water, regardless of the sealer used (Table 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the TW groups, it was observed a static difference between the response of Control and Sealapex (p\u0026lt;0.001), and AH Plus and Sealapex at 30 days (p\u0026lt;0.001). For the TM groups, it was observed a difference between Endofill and AH Plus (p\u0026lt;0.001), and Sealapex and AH Plus at 5 days (p\u0026lt;0.001) and Control and Sealapex at 30 days (p=0.001). Considering each tube\u0026rsquo;s response according to the supplementation with melatonin or water, it was observed a lower immunolabeling in the AH Plus group at 5 (p=0.038), 15 (p=0.002) and 30 days (p=0.002) when the melatonin was used (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCollagen Maturity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRepresentative images from Picrosirius red staining to identify the maturity of collagen fibres for all groups are shown in Figure 4. According to Mann-Whitney statistical tests between all groups with melatonin supplementation versus all groups with water supplementation, it can be observed a higher percentage of mature fibres in the groups supplemented with melatonin at 5 days (p=0.024). On the other hand, in the TW groups, the percentage of immature was a higher at 5 days (p=0.024). In the comparative analysis among all TW groups at 5 days, the AH plus group showed more mature fibres compared to Sealapex (p=0.036) and, at 15 days, the Control group showed more mature fibres compared to Endofill (p=0.029). The comparative analysis among all TM groups at 5 days, revealed that control and Endofill tubes had a higher percentage of mature fibres than Sealapex and AH Plus (p\u0026lt;0.001). However, there were no statistical differences between them (p\u0026gt;0.05). At 30 days there were more mature fibres in the AH Plus and Endofill when compared to the control tube (p=0.005), also with no statistical difference between them. The comparison for each group with supplementation of melatonin or water enable to observe differences in the Control group at 5 days (p\u0026lt;0.001), in the AH Plus group (p=0.011) at 30 days, and in the Endofill group at 5 days (p=0.021), which presented a higher number of mature fibres in the presence of melatonin. On the other hand, the control group, at 15 days, showed higher immature fibres in the presence of melatonin (p=0.015), (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCalcium deposition\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRepresentative images from the Von Kossa staining and birefringent to Polarized light to identify calcium-positive structures for all groups are showed in Figures 5 and 6.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor Sealapex endodontic sealer, the presence of calcium deposits in von Kossa staining (Figure 5) and birefringent to polarized light (Figure 6) was observed in all periods of analysis, regardless of supplementation of melatonin. For AH Plus, Endofill, as well as in the control tube, it was not observed any sign of these structures, both in TW groups or TM groups (Table 4)\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAfter being cleaned and shaped, the root canal must be filled with specific materials, the gutta-percha and endodontic sealers [1, 36]. However, these biomaterials when in contact with periapical tissues can induce inflammatory conditions that can even interfere negatively with the periapical repair\u0026nbsp;[4, 8]. Studies suggest that melatonin has an anti-inflammatory ability, with that knowledge, this study evaluated the influence of melatonin\u0026nbsp;supplementation on the tissue response of endodontic sealers. The results showed that melatonin\u0026nbsp;was able to decrease the inflammatory infiltrate and stimulate the repair process and did not inhibit calcium deposition in tissues, which rejects partially our null hypothesis.\u003c/p\u003e\n\u003cp\u003eMelatonin is a hormone produced especially in the pineal gland. Although its main action is to regulate the circadian rhythm [34], this molecule can modulate the inflammatory process, besides regulating the oxidative stress and the proliferation of tumoral cells [15, 16, 24]. These effects are due to its ability to penetrate cells, acting on their DNA and cell structures, such as the plasma membrane [37,38}. A previous study review has shown that melatonin can reduce inflammation in dental clinical conditions [24]. Thus, melatonin may be considered as a potential reducer of the inflammatory process induced by endodontic sealers. Moreover, to enhance the effects of the melatonin in this study, a prophylactic supplementation dose was administered to increase the concentrations of melatonin molecules in the rats, preparing the organism of the experimental animals when getting in contact with the endodontic sealers [39].\u003c/p\u003e\n\u003cp\u003eThe evaluation of tissue responses induced by biomaterials can be observed by implanting standardized polyethylene tubes filled with specific materials into the subcutaneous tissue of rats [29, 32, 33].\u0026nbsp;The staining of hematoxylin and eosin can show the expression of inflammatory cells indicating the intensity of inflammation [4, 29, 40]. Three different periods of analysis were considered in this project, making it possible to observe a reduction of the inflammatory response of sealers over time, which is referenced in the literature as a natural process promoted by endodontic sealers [4]. However, when was made a comparison between the groups that had the supplementation of melatonin and the group that was supplemented with the vehicle (water), a notable difference was observed, mainly at 30 days, having a lower inflammation in Endoffill and Selapex groups. Endofill is an oxide zinc-based endodontic sealer, whose capacity to induce inflammation is extremely high [8], which could be observed in the TW group, having the Endofill expressing a very intense inflammatory infiltrate. On the other hand, in TM no difference was observed in the inflammatory infiltrate among the different groups of sealers and the control tube, which shows the reduction of the inflammation. In addition, to provide additional evidence about the inflammatory response of the sealers associated with the supplementation of a potential anti-inflammatory substance, the immunolabeling of IL-6 and TNF-\u0026alpha;\u0026nbsp;was done [41]. These inflammatory mediators are associated with the regulation of the inflammation, inducing, and modulating it. The IL-6 is produced by several cells, especially by the T-cells and it also can be very easily found in acute responses it has been reported as an interleukin that increases in high levels when tissues are in contact with endodontic sealers [42, 43] For the TNF-\u0026alpha;, it is a protein able to recruit inflammatory cells and induce the production of pro and pre inflammatory mediators, being present in every step of the inflammatory process [44]. Consequently, knowing all this information and associating it with its relation to endodontic sealer tissue\u0026rsquo;s response, the assessment of the immunolabeling of these mediators is considered a particularly important aspect. [43, 45].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAccording to the findings of the immunohistochemistry analysis, there was an increase of these mediators in the first period of analysis followed by a decrease of them over time, which was expected, since the inflammatory infiltrate is elevated in the beginning, contributing to the proliferation of inflammatory cells, such as lymphocytes and macrophages, which can produce these cytokines [29, 43]. However, when melatonin was supplemented, the immunolabeling of TNF-\u0026alpha;\u0026nbsp;and\u0026nbsp;IL-6 was lower even in initial periods. In addition, in the group of sealers that received melatonin, no statistical difference was observed among them for IL-6. The results prove that melatonin has the potential to decrease the inflammatory process by the regulation of the expression of this type of cytokines [24, 42-44]. Still, to investigate even more these associations, more studies must be conducted to understand the interrelation between these pro-inflammatory mediators and the response promoted by endodontic sealers.\u003c/p\u003e\n\u003cp\u003eThe type of collagen fibres expressed in the tissues can contribute to the understanding of a biomaterial tissue\u0026rsquo;s response. It is known that after the inflammation is controlled, there are a proliferation of fibroblasts cells that migrate to the area injured. \u0026nbsp;These cells produce collagen that can be classified in mature, typically found in areas that suffered irritation for longer periods and immature fibres, associated with tissues that are in the beginning of the repair process [46]. The Picrosirus red is a technique that enable to detect the maturity of collagen fibres that are being expressed in the analysed area [29]. After the staining, the detection of mature fibres is seen in a variation of red color and the immature fibres in a variation of green, both in polarized light microscopy [29]. Despite being frequently found in parts that are initializing the repair process, the immature fibres can be also verified in areas going through remodeling process [47]. However, in this study it was observed a higher expression of mature fibres over time in the groups that had the supplementation of melatonin when compared to the groups that were supplemented with water. Therefore, associating to the fact that the melatonin has the ability of decreasing the inflammation in tissues [15,16] and it has the ability of influencing in the deposition of collagen [48]. The association of the results of this experiment and the knowledge provided by the literature, it is possible to say that the expression of more mature fibres was due the maturity of the inflammatory process, which shows tissues renewal indicating its domination by the rat\u0026rsquo;s immunologic system [15,16]. Although it was possible to evaluate an amelioration of repairment, it is suggested immunohistochemistry analyzes to consolidate the type of collagen in the different periods to understand in which phase the repair would be.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSome endodontic sealers, especially those that contain calcium hydroxide in their composition, have the capacity of allowing calcium deposition in tissues, which can be interpreted as the beginning of a mineralization process [40]. These characteristics could also be evaluated in this study by the von Kossa staining, with the expression of calcium carbonate and Polarized light, with the identification of areas with birefringent calcium crystals [29]. Sealapex was the only sealer that had in its composition the calcium hydroxide and the other materials were not based on calcium inducers; thus, as expected, the only sealer that promoted calcification in all periods was Sealapex [40], revealing that melatonin did not interfere in the biomineralization process.\u003c/p\u003e\n\u003cp\u003eThese data attest that melatonin was able to modulate the inflammatory process, decreasing the inflammatory infiltrate, the immunolabeling of cytokines, such as TNF-\u0026alpha; and IL-6; also, it probably accelerates the remodeling process and do not influence in the biomineralization process. Such remarkable results could be further explored in dentistry, enabling the amelioration of endodontics treatments and the knowledge of clinicians and researchers.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIt can be concluded that melatonin modulated the inflammatory process, decreasing inflammation and the immunolabeling of IL-6 and TNF, stimulating tissue repair and did not influence in calcium deposition.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePedro Henrique Chaves de Oliveira:\u0026nbsp;\u003c/strong\u003eResponsible for conducting the project, organizing the experiments and laboratories procedures, collection of data, run the statistics, interpreted the results and wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMichael J\u0026uacute;nio da Silva Rodrigues:\u0026nbsp;\u003c/strong\u003eResponsible for organizing the laboratory experiments, staining of the blades and taking pictures to obtain the results.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCristiane Cantiga da Silva:\u0026nbsp;\u003c/strong\u003eDuring all the project helped carrying the animals, organized the experiments, participated in the staining process, helped running the statistics and collaborated in the review of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCarolina de Barros Morais Cardoso:\u0026nbsp;\u003c/strong\u003eResponsible for helping to organize the experiment procedures, collect the data e review the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFl\u0026aacute;vio Duarte Faria:\u0026nbsp;\u003c/strong\u003eResponsible for helping to organize the experiment procedures, collect the data e review the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLeopoldo Cosme da Silva:\u0026nbsp;\u003c/strong\u003eResponsible to execute the surgical procedure, to organize the results obtained and in the review of the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEdilson Ervolino:\u0026nbsp;\u003c/strong\u003eResponsible for conducting the immunohistochemistry staining, contributed to the comprehension of the results obtained, especially for the inflammatory mediators and maturity of collagen and reviewed the manuscript as well.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLuciano Tavares Angelo Cintra:\u0026nbsp;\u003c/strong\u003eResponsible for supervising all the experiment, laboratory procedures, data collection, manuscript writing, reviewed the statistics and helped in the understanding of the results obtained.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical Principals of Animal Experimentation and its implantation was approved by CEUA - (Protocol FOA no. 00433-2018), S\u0026atilde;o Paulo State University (Unesp), Ara\u0026ccedil;atuba, SP, Brazil.\u003c/p\u003e\n\u003cp\u003eThe study was with animals, for that reason the only consent needed was from the local ethical committee\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunda\u0026ccedil;\u0026atilde;o de Amparo \u0026agrave; Pesquisa do Estado de S\u0026atilde;o Paulo (Process no. 2017/24713-7)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors deny any conflicts of interest related to this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e\u0026Oslash;rstavik D (2014) Endodontic filling materials. Endod Top 31:53\u0026ndash; 67.\u003c/li\u003e\n\u003cli\u003eGuttuso J (1963) Histopathologic study of rat connective tissue responses to endodontic materials. Oral Surg Oral Med Oral Pathol 6:713-27.\u003c/li\u003e\n\u003cli\u003eMorse DR, Martell B, Pike CG, Fantasia J, Esposito JV, Furst ML (1984) A comparative tissue toxicity evaluation of Gutta-percha root canal sealers. Part II. Forty-eight-hour findings. J Endod 10:484-6.\u003c/li\u003e\n\u003cli\u003eBenetti F, Queiroz IOA, Oliveira PHC, Conti LC, Azuma MM, Oliveira SHP, Cintra LTA (2019) Cytotoxicity and biocompatibility of a new bioceramic endodontic sealer containg calcium hydroxide. Brazilian of Oral Research 33; e42\u003c/li\u003e\n\u003cli\u003eGeurtsen W (2001). Biocompatibility of root canal filling materials. Aust Endod J 27(1):12-21. doi: 10.1111/j.1747-4477.2001.tb00445.x. PMID: 11481874.\u003c/li\u003e\n\u003cli\u003eKim YK, Grandini S, Ames JM, Gu LS, Kim SK, Pashley DH et al (2010) Critical review on methacrylate resin-based root canal sealers. J Endod 36(3):383-99.\u003c/li\u003e\n\u003cli\u003eSilva Almeida LH, Moraes RR, Morgental RD, Pappen FG (2017) Are Premixed Calcium Silicate-based Endodontic Sealers Comparable to Conventional Materials? A Systematic Review of In Vitro Studies. J Endod 43(4):527-535. doi: 10.1016/j.joen.2016.11.019. Epub 2017 Feb 16. PMID: 28216270.\u003c/li\u003e\n\u003cli\u003eZmener O, Lalis RM, Pameijer CH, Chaves C, Kokubu G, Grana D (2012) Reaction of rat subcutaneous connective tissue to a mineral trioxide aggregate-based and a zinc oxide and eugenol sealer. J Endodontics 38:1233-1238.\u003c/li\u003e\n\u003cli\u003eSlominski R M, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT (2012) Melatonin membrane receptors in peripheral tissues, distribution and functions. Molecular and Cellular Endocrinology 351:152-166.\u003c/li\u003e\n\u003cli\u003eAzuma MM, Gomes-Fiho JE, Ervolino E, Pipa CB, Cardoso CBM, Andrada AC, Kawai T, Cintra LTA (2017) Omega 3 fatty acids reduce bon\u0026eacute; resorption while promoting bon\u0026eacute; generation in rat apical periodontitis. J Endod 43:970-76.\u003c/li\u003e\n\u003cli\u003eNoori-Hassanvan M, Soleimani Mehranjani M, Shojafar E (2017) Melatonin improves the structure and function of autografted mice ovaries through reducing inflammation: A stereologican and biochemical analysis. International Immunopharmacology 74:105679.\u003c/li\u003e\n\u003cli\u003eReiter RJ, Tan DX, Korkmaz A (2009) The circadian melatonin rhythm and its modulation: possible impact on hypertension. Journal of Hypertension Supplement 27;S17-S20.\u003c/li\u003e\n\u003cli\u003eSingh M, Jadhav HR (2014) Melatonin: functions and ligands. Drug Discovery Today 19:1410\u0026ndash;1418.\u003c/li\u003e\n\u003cli\u003eAcu\u0026ntilde;a-Castroviejo D, Escames G, Venegas C et al. (2014) Extrapineal melatonin: sources, regulation, and potential functions. Cellular and Molecular Life Sciences 71:2997\u0026ndash;3025.\u003c/li\u003e\n\u003cli\u003eMauriz JL, Collado PS, Vaneroso C, Reiter RJ, Gonz\u0026aacute;les-Gallego J (2013) A review of the molecular aspectes of melatonin\u0026rsquo;s anti-inflamatory actions: recent insights and new perspectives. Journal of Pineal Research 54:1-14. \u003c/li\u003e\n\u003cli\u003eDong Y, Fan C, Hu W, et al (2016) Melatonin attenuated early brain injury induces by sbarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling. Journal of Pineal Research. 60:253-262.\u003c/li\u003e\n\u003cli\u003eColares JR, Schemitt EG, Hartmann RM, Licks F, Soares MD, Bosco AD, Marroni NP (2016) Antioxidant and anti-inflammatory action of melatonin in an experimental model of secondary biliary cirrhosis induced by bile duct ligation. World J. Gastroenterol 22:8918-8928.\u003c/li\u003e\n\u003cli\u003eOstjen CA, Rosa CGS, Hartmann RM, Schemitt EG, Colares JR, Marroni NP (2019) Anti-inflammatory and antioxidant effect of melatonin on recovery from muscular trauma induced in rats. Exp Mol Pathol. 106:52-59.\u003c/li\u003e\n\u003cli\u003eBaeuerle PA, Baltimore D (1996) NF-Kappa B: ten years after. Cell 87:13-20.\u003c/li\u003e\n\u003cli\u003eReiter RJ, Calvo JR, Karbownik M, Qi W, Tan DX(2000) Melatonin and its relation to the immune system and inflammation. Ann N Y Acad Sci 917:376-86. \u003c/li\u003e\n\u003cli\u003eCuzzocrea S, Reiter RJ (2001) Pharmacological action of melatonin in shock, inflammation and ischemia/reperfusion injury. Eur J Pharmacol 24;426(1-2):1-10. \u003c/li\u003e\n\u003cli\u003eVriend J, Reiter RJ (2014) Melatonin as a proteasome inhibitor. Is there any clinical evidence? Life Sciences 115:8-14.\u003c/li\u003e\n\u003cli\u003eFavero G, Franseschetti L, Bonomini F, Rodella LF, Rezzani.R (2017) Melatonin as Anti-Inflamatory angent modulating inflammasome activation. Int J Endocrinol 2017:1835-195.\u003c/li\u003e\n\u003cli\u003ede Oliveira PHC, Lemos CAA, Cantiga-Silva C, Faria FD, Cintra LTA, Pellizzer EP (2021) Melatonin as an adjunctive treatment on dental procedures: A systematic review. Oral Dis. \u003cem\u003e28\u003c/em\u003e:1770\u0026ndash;1782. doi: 10.1111/odi.13941. \u003c/li\u003e\n\u003cli\u003eLe\u0026oacute;n J, Casado J, Jim\u0026eacute;nez Ruiz SM, et al (2014) Melatonin reduces endothelin-1 expression and secretion in colon cancer cells through the inactivation of FoxO-1 and NF-\u0026kappa;\u0026beta;. \u003cem\u003eJ Pineal Res\u003c/em\u003e. 56:415-426. doi:10.1111/jpi.12131 \u003c/li\u003e\n\u003cli\u003eHabtemariam S, Daglia M, Sureda A, Selamoglu Z, Gulhan MF, Nabavi SM (2017) Melatonin and respiratory diseases: a review. Current Topics in Medicinal Chemistry 17:467-488.\u003c/li\u003e\n\u003cli\u003ede Oliveira PHC, Gomes Filho JE, Rodrigues MJDS, da Silva CC, Cardoso CDBM, Cosme daSilva L, Ervolino E, Cintra LTA (2022) Influence of supplement administration of omega-3 on the subcutaneous tissue response of endodontic sealers in Wistar rats. Int Endod J. 55:1026-1041. doi: 10.1111/iej.13795. Epub 2022 Jul 16. PMID: 35791796.\u003c/li\u003e\n\u003cli\u003eNagendrababu V, Kishen A, Murray PE, et al (2021) PRIASE 2021 guidelines for reporting animal studies in Endodontology: a consensus-based development. \u003cem\u003eInt Endod J\u003c/em\u003e. 54:848-857. \u003c/li\u003e\n\u003cli\u003eCintra LTA, Benetti F, de Azevedo Queiroz \u0026Iacute;O, de Ara\u0026uacute;jo Lopes JM, Penha de Oliveira SH, Sivieri Ara\u0026uacute;jo G, Gomes-Filho JE (2017a) Cytotoxicity, Biocompatibility, and Biomineralization of the New High-plasticity MTA Material. J Endod 43:774-778. \u003c/li\u003e\n\u003cli\u003eSantos M, Favero G, Bonomini F, Stacchiotti A, Rodella LF, Veronese FV, Rezzani R (2017) Oral supplementation of melatonin protects against lupus nephritis renal injury in a pristane-induced lupus mouse model. Life Sciences 193:242-251\u003c/li\u003e\n\u003cli\u003eLi JG, Lin JJ, Wang ZL, Cai WK, Wang PN, Jia Q, Zhang AS, Wu GY, Zhu GX, Ni LX. (2015) Melatonin attenuates inflammation of acute pulpitis subjected to dental pulp injury. Am J Transl Res 7;166-78.\u003c/li\u003e\n\u003cli\u003eISO 10993-6. Biological evaluation of medical devices. Part 6: Tests for local effects nafter implantation International Standard Norm, Porto, Portugal (2007).\u003c/li\u003e\n\u003cli\u003eISO 10993-7. Biological evaluation of medical devices. Part 7: Ethylene oxide sterilization residuals. International Standard Norm, Porto, Portugal (2008).\u003c/li\u003e\n\u003cli\u003eGomes-Filho JE, Duarte PC, de Oliveira CB, Watanabe S, Lodi CS, Cintra LT, Bernab\u0026eacute; PF (2012) Tissue reaction to a triantibiotic paste used for endodontic tissue self-regeneration of nonvital immature permanent teeth. J Endod 38:91-4. \u003c/li\u003e\n\u003cli\u003eBenetti F, Briso ALF, Ferreira LL, Carminatti M, Alamo L, Ervolino E, Dezan-J\u0026uacute;nior E, Cintra LTA (2018) In Vivo Study of the Action of a Topical Anti-Inflammatory Drug In Rat Teeth Submitted To Dental Bleaching. Braz. Dent. J 29;555-561. \u003c/li\u003e\n\u003cli\u003eSadr S, Golmoradizadeh A, Raoof M, Tabanfar MJ (2015) Microleakage of Single-Cone Gutta-Percha Obturation Technique in Combination with Different Types of Sealers. Iran Endod J 10(3):199-203. \u003c/li\u003e\n\u003cli\u003eTan DX, Reiter RJ, Chen LD, Poggeler B, Poeggeler B, Manchester LC, Barlow-Walden LR (2011) Pharmacological levels of melatonin reduce DNA adduct formation. Both Physiological and Mol Cell Biochem 353:139\u0026ndash;149. \u003c/li\u003e\n\u003cli\u003eMelchiorii D, Reiter RJ, Attia A, Hara M, Burgos A, Nistico G (1995) Potent protective effect melatonin on in vivo paraquat induced toxicity. Life Sci 56:83\u0026ndash;88\u003c/li\u003e\n\u003cli\u003eRenn TY, Huang YK, Feng SW, Wang HW, Lee WF, Lin CT, Burnouf T, Chen LY, Kao PF, Chang HM (2018) Prophylactic supplement with melatonin successfully suppres the pathogenesis of periodontitis though mormalizing RANKL/OPG ratio and depressing the TLR4/MyD88 signaling pathway. J. Pineal Res 64:e12464\u003c/li\u003e\n\u003cli\u003eBueno CR, Valentim D, Marques VAS., Gomes-Filho JE, Cintra LTA, Jacinto RC, Dezan-Junio E (2016) Biocompatibility and biomineralizantion assessment of bioceramic, epoxy, and calcium hydroxide-based sealers. Braz. Oral Res 30:1-9.\u003c/li\u003e\n\u003cli\u003eNibali L, Fedele S, D\u0026apos;Aiuto F, Donos N (2012) Interleukin-6 in oral diseases: a review. Oral Dis 8: 236-43.\u003c/li\u003e\n\u003cli\u003eHeinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newer G, Schaper F (2003) Principles of interleukin (IL-6) type cytokine signaling and its regulation. Biochemical J 374:1-20.\u003c/li\u003e\n\u003cli\u003eSilva GF, Tanomaru-Filho M, Bernardi MI, et al (2015) Niobium pentoxide as radiopacifying agent calcium silicate-based material: evaluation of physicochemical and biological properties. Clin Oral Investig 19:2012\u0026ndash;25\u003c/li\u003e\n\u003cli\u003ePfeffer K (2003) Biological functions of tumor necrosis factor cytokines and their receptors. Cytok Growth Fact Rev 14:185-91\u003c/li\u003e\n\u003cli\u003eChang et al 2015\u003c/li\u003e\n\u003cli\u003eDiegelmann RF, Evans MC (2004) Wound healing: an overview of acute, fibrotic and delayed healing. Front Biosci 9:283-9.\u003c/li\u003e\n\u003cli\u003eZerbinati N, Calligaro A (2018) Calcium hydroxylapatite treatment of human skin: evidence of collagen turnover through picrosirus red staining and circularly polarized microscopy. Clin Cosmet Investig Dermatol 11:29-35.\u003c/li\u003e\n\u003cli\u003eBona S, Rodrigues G, Moreira AJ, Di Naso FC, Dias AS, Da Silveira TR, Marroni CA, Marroni NP (2018) Antifibrogenic effect of melatonin in rats with experimental liver cirrhosis induced by carbon tetrachloride. JGH Open. 2:117-123. doi: 10.1002/jgh3.12055. PMID: 30483575; PMCID: PMC6206983.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Scores observed for inflammatory response of endodontic sealers and oral supplementation of Melatonin\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.309278350515465%\" rowspan=\"2\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePeriod of analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.185567010309279%\" rowspan=\"2\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eScore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"72.16494845360825%\" colspan=\"8\" style=\"width: 56.7737%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eH.E. Staining for Groups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.0618556701030926%\" valign=\"top\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.4935064935064934%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl + Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.4935064935064934%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAH Plus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.584415584415584%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAH Plus + Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.4935064935064934%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndofill\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndofill + Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.792207792207792%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSealapex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSealapex+ Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.5974025974025974%\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.75268817204301%\" rowspan=\"5\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e5 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.903225806451612%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.150537634408602%\" valign=\"top\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"top\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003ep\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003eMedian**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e3,5\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e3,5\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e4\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e2,5\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e4\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e3,5\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e3,5\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e3\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.75268817204301%\" rowspan=\"5\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e15 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.903225806451612%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.150537634408602%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2/8 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003ep=0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003eMedian**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e4\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2,5\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.75268817204301%\" rowspan=\"5\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e30 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.903225806451612%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e0 /8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.150537634408602%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e4/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e1/8 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003ep\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"top\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.4208%;\"\u003e\n \u003cp\u003eMedian**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3225%;\"\u003e\n \u003cp\u003e1,5\u003csup\u003eAc\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0553%;\"\u003e\n \u003cp\u003e2,5\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5468%;\"\u003e\n \u003cp\u003e2,5\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.4915%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e2\u003csup\u003eBb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.0829%;\"\u003e\n \u003cp\u003e2,5\u003csup\u003eAab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.7864%;\"\u003e\n \u003cp\u003e1\u003csup\u003eBab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"top\" style=\"width: 6.6743%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e** Superscript\u0026nbsp;uppercase for analysis into different sealers supplemented with water or into different sealers supplemented with melatonin. Supperscript lower case letters for two groups analysis (Control versus Control + Melatonin; AH Plus versus AH Plus + Melatonin; Endofill versus Endofill + Melatonin; Sealapex versus Sealapex + Melatonin)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Scores observed for the expression of IL-6 by endodontic sealers with and without the supplementation of melatonin.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.473684210526315%\" rowspan=\"2\" style=\"width: 6.6258%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePeriod of analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.315789473684211%\" rowspan=\"2\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eScore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"69.47368421052632%\" colspan=\"8\" style=\"width: 56.4487%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eIL-6. Staining for Groups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.368421052631579%\" valign=\"top\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.792207792207792%\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.987012987012987%\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl + Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.194805194805195%\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAH Plus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.987012987012987%\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAH Plus + Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.792207792207792%\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndofill\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.987012987012987%\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndofill + Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.090909090909092%\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSealapex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.987012987012987%\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSealapex+ Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.090909090909092%\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.782608695652174%\" rowspan=\"5\" style=\"width: 6.6258%;\"\u003e\n \u003cp\u003e5 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.521739130434782%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.521739130434782%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.521739130434782%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.608695652173913%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.608695652173913%\" valign=\"top\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e\u0026nbsp;2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"top\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e3//8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003ep\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003eMedian**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e4\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e3\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e4\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e4\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e3\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e3\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.782608695652174%\" rowspan=\"5\" style=\"width: 6.6258%;\"\u003e\n \u003cp\u003e15 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.521739130434782%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.521739130434782%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.521739130434782%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.608695652173913%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.608695652173913%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e7/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e7/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003ep=0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003eMedian**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e4\u003csup\u003eAab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e3\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAc\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e3\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e3\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"9.782608695652174%\" rowspan=\"5\" style=\"width: 6.6258%;\"\u003e\n \u003cp\u003e30 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.521739130434782%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.521739130434782%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.3478260869565215%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.521739130434782%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e0 /8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.608695652173913%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.869565217391305%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.608695652173913%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003ep\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"top\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.7119%;\"\u003e\n \u003cp\u003eMedian**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.6793%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e3\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.819277108433735%\" valign=\"bottom\" style=\"width: 3.528%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" valign=\"bottom\" style=\"width: 5.9374%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"bottom\" style=\"width: 6.5398%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.048192771084338%\" valign=\"bottom\" style=\"width: 8.691%;\"\u003e\n \u003cp\u003e2\u003csup\u003eBa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.433734939759036%\" valign=\"top\" style=\"width: 6.97%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e** Superscript uppercase for analysis into different sealers supplemented with water or into different sealers supplemented with melatonin. Supperscript lower case letters for two groups analysis (Control versus Control + Melatonin; AH Plus versus AH Plus\u0026nbsp;+ Melatonin; Endofill versus Endofill + Melatonin; Sealapex versus Sealapex + Melatonin)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Scores observed for the immunolabeling of TNF-\u0026alpha; by endodontic sealers with and without the supplementation of melatonin.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.309278350515465%\" rowspan=\"2\" style=\"width: 6.6987%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePeriod of analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.185567010309279%\" rowspan=\"2\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eScore\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"72.16494845360825%\" colspan=\"8\" style=\"width: 55.6778%;\"\u003e\n \u003cp\u003eTNF-\u0026alpha; \u003cstrong\u003eStaining for Groups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.0618556701030926%\" valign=\"top\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"6.4935064935064934%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControl + Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.4935064935064934%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAH Plus\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.584415584415584%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAH Plus + Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.4935064935064934%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndofill\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndofill + Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.792207792207792%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSealapex\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSealapex+ Melatonin\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.5974025974025974%\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.75268817204301%\" rowspan=\"5\" style=\"width: 6.6987%;\"\u003e\n \u003cp\u003e5 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.903225806451612%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.150537634408602%\" valign=\"top\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e7/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"top\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003ep\u0026lt;0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003eMedian**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e3,5\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e3,5\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e3\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e2\u003csup\u003eAbc\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e3\u003csup\u003eBb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAc\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e3\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.75268817204301%\" rowspan=\"5\" style=\"width: 6.6987%;\"\u003e\n \u003cp\u003e15 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.903225806451612%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.150537634408602%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e7/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e6/8 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003ep=0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003eMedian**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e3\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e3\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e2\u003csup\u003eAb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e3\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e3\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e2\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.75268817204301%\" rowspan=\"5\" style=\"width: 6.6987%;\"\u003e\n \u003cp\u003e30 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.903225806451612%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.376344086021505%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e0 /8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.451612903225806%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.827956989247312%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.150537634408602%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e7/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e2/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e5/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e7/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e8/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e1/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e6/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e0/8 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"bottom\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003eP=0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e3/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e0/8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"top\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.5247%;\"\u003e\n \u003cp\u003eMedian**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.3938%;\"\u003e\n \u003cp\u003e3\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e3\u003csup\u003eAa\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 4.0888%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;2\u003csup\u003eBac\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.457831325301205%\" style=\"width: 9.5696%;\"\u003e\n \u003cp\u003e2\u003csup\u003eAab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.024096385542169%\" style=\"width: 5.5678%;\"\u003e\n \u003cp\u003e3\u003csup\u003eBabc\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 8.8737%;\"\u003e\n \u003cp\u003e2\u003csup\u003eAab\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.228915662650603%\" style=\"width: 6.1768%;\"\u003e\n \u003cp\u003e2\u003csup\u003eBb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.25301204819277%\" style=\"width: 7.2207%;\"\u003e\n \u003cp\u003e2\u003csup\u003eAb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"2.4096385542168677%\" valign=\"top\" style=\"width: 8.0907%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e** Superscript uppercase for analysis into different sealers supplemented with water or into different sealers supplemented with melatonin. Supperscript lower case letters for two groups analysis (Control versus Control + Melatonin; AH Plus versus AH Plus + Melatonin; Endofill versus Endofill + Melatonin; Sealapex versus Sealapex + Melatonin)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Median of mature and immature fibers and mineralization capacity for each sealer in both experimental groups (Results on %)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGroups\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eTime\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMaterial\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCollagen Maturity (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMineralization (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMature Fibers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eImature Fibers\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVK\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePOL\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"12\" valign=\"top\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e05 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e52.697\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e47.303\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAH Plus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e66.158\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33.842\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEndofill\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e61.065\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38.935\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSealapex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e39.223\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e60.777\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e15 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e65.508\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e34.492\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAH Plus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e64.982\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e35.018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEndofill\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e47.279\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e52.721\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSealapex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e51.587\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e48.413\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e30 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e69.665\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e30.335\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAH Plus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e56.260\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e43.740\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEndofill\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e61.686\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38.314\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSealapex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e78.405\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e21.595\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"12\" valign=\"top\"\u003e\n \u003cp\u003eMelatonin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e05 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e80.029\u003csup\u003eAb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e19.971\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAH Plus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e55.311\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e44.681\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEndofill\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e81.923\u003csup\u003eAb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e18.077\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSealapex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e50.441\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e49.559\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e15 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e52.810\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e47.190\u003csup\u003e\u0026nbsp;b\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAH Plus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e59.995\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e40.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEndofill\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e45.185\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e54.815\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSealapex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e55.357\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e44.643\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003e30 days\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e48.862\u003csup\u003eA\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e51.138\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAH Plus\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e84.011\u003csup\u003eBb\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e15.989\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEndofill\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e74.249\u003csup\u003eB\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e25.751\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSealapex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e66.823\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33.177\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* Superscript capital letters represent statistical diferences among the melatonin supplemented groups or water supplemented groups in each period (analysis among 4 groups)\u003c/p\u003e\n\u003cp\u003e* Superscript lowercase letters for two groups in each period of analysis by Mature and Imature Fibers (Control versus Control + melatonin; AH Plus versus AH Plus + melatonin; Endofill versus Endofill + melatonin; Sealapex versus Sealapex + melatonin)\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"dodontic sealers, tissue response, inflammation, mineralization, melatonin","lastPublishedDoi":"10.21203/rs.3.rs-3649915/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3649915/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives:\u003c/strong\u003e Evaluate the influence of melatonin supplementation on tissue’s response to endodontic sealers in Wistar rats.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMaterial and methods:\u003c/strong\u003e Forty-eight Wistar rats had four polyethylene tubes implanted in their subcutaneous tissue, one empty (control) and three filled with endodontic sealers (AH Plus, Endofill and Sealapex). Half of the animals were supplemented with melatonin (TM) and the remaining with water (TW) for 15 days before the implantation until euthanasia. After 5, 15 and 30 days (n=8/group/period) tubes were removed and analyzed in H\u0026amp;E, immunohistochemistry, PSR, VK and POL. The results were statistically analyzed (p\u0026lt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eIn TW, Endofill evoked a more intense inflammatory infiltrate compared to AH Plus and control in 30-day (p\u0026lt;0.05). In TM tubes, there was any difference in both periods (p\u0026gt;0.05), differences for Endofill (p=0.05) and Sealapex (p\u0026lt;0.05) was observed in TM animals in 30-day, presenting lower inflammatory infiltrate. For IL-6 and TNF-α it was observed that the immunolabeling was lower in TM animals in all periods, despite of the sealer. In addition, there was a higher percentage of mature fibers in TM groups at 5 days (p\u0026lt;0.05). Structures positive for von Kossa staining and birefringent to polarized light were observed only for Sealapex in all periods, regardless of melatonin supplementation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Melatonin influences inflammatory response of endodontic sealers, by modulating the inflammatory process and pre-inflammatory mediators, and stimulating tissue repair, without interfering on calcium deposition.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Relevance: \u003c/strong\u003eEvidence that melatonin can regulate inflammatory responses after the contact of tissues with biomaterials.\u003c/p\u003e","manuscriptTitle":"Influence of melatonin supplementation on tissue response of endodontic sealers in Wistar rats","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-12-02 00:55:42","doi":"10.21203/rs.3.rs-3649915/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c400e2d7-25f6-465b-90ce-1f0c831347e9","owner":[],"postedDate":"December 2nd, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-12-16T14:44:15+00:00","versionOfRecord":[],"versionCreatedAt":"2023-12-02 00:55:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3649915","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3649915","identity":"rs-3649915","version":["v1"]},"buildId":"-D5TCW68w8eVRRLyjaTIo","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}