Weber NC, Stursberg J, Wirthle NM, Toma O, Schlack W, Preckel B. Xenon preconditioning differently regulates p44/42 MAPK (ERK 1/2) and p46/54 MAPK (JNK 1/2 and 3) in vivo. Xenon may decrease the antihypertensive activities of Acebutolol. See how Contraindications & Blackbox Warnings Avoid life-threatening adverse drug events & improve clinical decision support. The present study illustrates the steps toward understanding molecular mechanism of xenon anesthesia by focusing on a link to the structures and spectra of intermolecular complexes of xenon. Luo Y, Ma D, Ieong E, Sanders RD, Yu B, Hossain M, Maze M. Xenon and sevoflurane protect against brain injury in a neonatal asphyxia model. The ePub format uses eBook readers, which have several "ease of reading" features Propofol, marketed as Diprivan, among other names, is a short-acting medication that results in a decreased level of consciousness and a lack of memory for events. Vizcaychipi MP, Lloyd DG, Wan Y, Palazzo MG, Maze M, Ma D. Xenon pretreatment may prevent early memory decline after isoflurane anesthesia and surgery in mice. It is still controversial whether an opioid system plays a role in antinociception induced by nitrous oxide. These findings were consistent in separate studies by Fahlenkamp et al.13 and Abramo et al.,9 as well as in a meta-analysis by Law et al.7 As Sanders et al. Absorption Inhaled Xenon Xe 133 Gas will enter the alveolar wall and enter the pulmonary venous circulation via the capillaries. Xenon acts on various neural receptors to cause anesthesia, and it is associated with better hemodynamic stability, lower toxicity and more potent analgesia than other anesthetics. Jordan BD, Wright EL. The six noble gases occurring naturally are helium (He), neon (Ne), argon (Ar), krypton (Kr), xenon (Xe), and the radioactive radon (Rn) [1]. the display of certain parts of an article in other eReaders. Learn more Pharmacodynamics Not Available Mechanism of action Not Available Absorption 4-6 franks and colleagues 4,5 demonstrated that 80% xenon reduced nmda-activated currents by approximately 60% (fig. The present study further elucidated the underlying molecular mechanism of xenon-induced preconditioning (Xe-PC) by focusing on a potential link of xenon to the cytoskeleton. The calculation is down by assuming a typical membrane thickness of about 10 nm and the results are shown in the unit of one million volts per meter with "-" and "+" indicating that the direction of electric field is respectively pointing outward or inward inside the neural membrane . Ma D, Hossain M, Pettet GK, Luo Y, Lim T, Akimov S, Sanders RD, Franks NP, Maze M. Xenon preconditioning reduces brain damage from neonatal asphyxia in rats. Xenon inhibits the plasma membrane Ca 2+ pump, 4 an action similar to that of volatile anesthetics, which may be responsible for an increase in neuronal Ca 2+ concentrations and altered excitability. As a general anesthetic, xenon possesses many advantages. In the study of Yamakura and Harris, their results showed N2O (0.58 atmosphere [atm]) and xenon (0.46atm) exhibited similar effects on various receptors, and the NMDA receptors, and nACh receptors composed of 2 subunits are likely targets for NO and xenon [11]. The risk or severity of hypertension can be increased when Aminophenazone is combined with Xenon. Future research should focus on reducing the incidence of PONV; lowering costs,11 which may involve changing priming and flushing practices;14 and evaluating the environmental impact of xenon when compared to greenhouse gases like nitrous oxide.4. Most of the Xenon Xe 133 that enters the circulation from a single breath is returned to the lungs and exhaled after a single pass through the peripheral circulation. In addition, xenon demonstrates many favorable pharmacodynamic and pharmacokinetic properties, which could be used in certain niche clinical settings such as cardiopulmonary bypass. Ischemic preconditioning was more effective than the anesthetics [35]. Yamakura T, Harris RA. In addition, it has been confirmed that xenon can confer neuroprotective [3] and cardioprotective [4,8] effects. Build, train, & validate predictive machine-learning models with structured datasets. You may switch to Article in classic view. Such knowledge is necessary to understand the performance of clinical nuclear medicine procedures, many drug-radiopharmaceutical interactions, and other causes of altered biodistribution. Xenon that is vented into the atmosphere is being returned to its original source, and thus environmental pollution is unlikely. With the development of technology, closed-circuit xenon delivery is introduced. 1 It was first created in the 1970s, and when it was first introduced to the market, it was difficult to synthesize and expensive. A primary cause of xenon anesthesia is attributed to inhibition of N-methyl-D-aspartate (NMDA) receptors by an unknown mechanism. Xenon Pharmaceuticals Inc.,Burnaby, BC, Canada BACKGROUND Major depressive disorder (MDD) is a highly prevalent mental health disorder and one of . The absence of an interaction does not necessarily mean no interactions exist. Xenon is a trace gas in Earths atmosphere and much more expensive than the lighter noble gases due to its very low concentration in air (0.5ppm) [2]. Inhaled Xenon Xe 133 Gas will enter the alveolar wall and enter the pulmonary venous circulation via the capillaries. Nitrous oxide, even at 80% concentration, does not quite produce surgical level anaesthesia in most people at standard atmospheric pressure, so it must be used as an adjunct anaesthetic, along with other agents. 81000493/H0906). Discover Part 6 of the Quality Data series: V09EX Other respiratory system diagnostic radiopharmaceuticals, Chronic Obstructive Pulmonary Disease (COPD), Predicted MS/MS Spectrum - 10V, Positive (Annotated), Predicted MS/MS Spectrum - 20V, Positive (Annotated), Predicted MS/MS Spectrum - 40V, Positive (Annotated), Predicted MS/MS Spectrum - 10V, Negative (Annotated), Predicted MS/MS Spectrum - 20V, Negative (Annotated), Predicted MS/MS Spectrum - 40V, Negative (Annotated). The most commonly usedantidepressants largely share the same mechanism of action. The anesthetic properties of xenon have been known for more than 50 yr, and the safety and efficacy of xenon inhalational anesthesia has been demonstrated in several recent clinical studies. The risk or severity of hypertension can be increased when Alclofenac is combined with Xenon. In the experimental myocardial infarction model, results showed combined isoflurane/xenon preconditioning reduced infarct size but not more than isoflurane alone. Xenon: Uses, Interactions, Mechanism of Action | DrugBank Online Xenon This drug entry is a stub and has not been fully annotated. This blockage inhibits the overstimulation of NMDA receptors, thus preventing their following downstream calcium accumulating cascades. Xenon may decrease the antihypertensive activities of Aliskiren. Mechanism of Action. Xenon Health is a physician-led management company that provides comprehensive anesthesia services nationwide. Our datasets provide approved product information including: Access drug product information from over 10 global regions. Pagel PS. Xenon-133 is an inhaled radionuclide used for lung imaging, imaging blood flow in the brain, and to assess pulmonary function. We are experimenting with display styles that make it easier to read articles in PMC. This was true in the xenon preconditioning [24,32-34]. Bantel C, Maze M, Trapp S. Neuronal preconditioning by inhalational anesthetics: evidence for the role of plasmalemmal adenosine triphosphate-sensitive potassium channels. Xenon as an anesthetic agent. Xenon has advantages over many other general anesthetics in the surgical setting. Sanders R, Franks N, Maze M. Xenon: no stranger to anaesthesia. Predicted MS/MS Spectrum - 10V, Positive (Annotated), Predicted MS/MS Spectrum - 20V, Positive (Annotated), Predicted MS/MS Spectrum - 40V, Positive (Annotated), Predicted MS/MS Spectrum - 10V, Negative (Annotated), Predicted MS/MS Spectrum - 20V, Negative (Annotated), Predicted MS/MS Spectrum - 40V, Negative (Annotated). These findings supported the contention that the protection of preconditioning with noble gases was independent of the anesthetic properties per se. Investigators also compared the protective effects of xenon preconditioning with those of ischemia, anesthetic(s) and hypoxia preconditioning. It passes through cell membranes and freely exchanges between blood and tissue. Weber NC, Toma O, Damla H, Wolter JI, Schlack W, Preckel B. Upstream signaling of protein kinase C-epsilon in xenon-induced pharmacological preconditioning. Suzuki T, Koyama H, Sugimoto M, Uchida I, Mashimo T. The diverse actions of volatile and gaseous anesthetics on human-cloned 5-hydroxytryptamine 3 receptors expressed in Xenopus oocytes. The risk or severity of hypertension can be increased when Acetylsalicylic acid is combined with Xenon. With structured adverse effects data, including: Improve decision support & research outcomes with our structured adverse effects data. In contrast with most inhalational anesthetics, the anesthetic gases xenon (Xe) and nitrous oxide (N(2)O) act by blocking the N-methyl-d-aspartate (NMDA) receptor. Cattano D, Valleggi S, Ma D, Kastsiuchenka O, Abramo A, Sun P, Cavazzana AO, Natale G, Maze M, Giunta F. Xenon induces transcription of ADNP in neonatal rat brain. In the rat N2O- and isoflurane-induced neuroapoptosis model, xenon preconditioning was found to prevent N2O oxide- and isoflurane-induced neuroapoptosis (in vivo and in vitro) and cognitive deterioration (in vivo). Xenon performs its anesthetic and neuroprotective functions through binding to glycine site of glutamatergic N-methyl-D-aspartate (NMDA) receptor competitively and blocking it. Moreover, xenon has been applied in the preconditioning, and the neuroprotective and cardioprotective effects of xenon preconditioning have been investigated in a lot of studies in which some mechanisms related to these protections are proposed. In the concentrations used for diagnostic purposes it is physiologically inactive. Pagel PS, Krolikowski JG, Pratt PF Jr, Shim YH, Amour J, Warltier DC, Weihrauch D. The mechanism of helium-induced preconditioning: a direct role for nitric oxide in rabbits. Suzuki T, Koyama H, Sugimoto M, Uchida I, Mashimo T. The diverse actions of volatile and gaseous anesthetics on human-cloned 5-hydroxytryptamine3 receptors expressed in Xenopus oocytes. In addition, the xenon induced anesthesia is related to the inhibition of the calcium ATPase pump on the cell membrane of synapses [13], which results from a conformational change when xenon binds to nonpolar sites inside the protein [14], and the non-specific interactions between the xenon and the lipid membrane [15]. Perturbation of oxygen pathways in membranes and proteins by anesthetic molecules and xenon atoms. Banks P, Franks NP, Dickinson R. Competitive inhibition at the glycine site of the N-methyl-D-aspartate receptor mediates xenon neuroprotection against hypoxia-ischemia. Sanders RD, Franks NP, Maze M. Xenon: No stranger to anaesthesia. Avoid life-threatening adverse drug events & improve clinical decision support. Action on neurotransmitters and their receptors is responsible for xenons anesthetic effect.4 Specifically, xenon is a potent, noncompetitive inhibitor of NmethylDaspartate (NMDA) receptors.4 Studies have also found that xenon can inhibit nicotinic acetylcholine receptors (nAChRs)5 or even specific serotonin receptors,6 though the latter has never been shown in humans.4 Some recent researchers have found that xenon activates particular potassium channels, which may contribute to its anesthetic actions.3 Xenon does not have an effect on gamma aminobutyric acid (GABA) receptors or non-NMDA glutamatergic receptors, such as the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.4 Lack of action at GABAA receptors is a common feature of xenon, nitrous oxide, cyclopropane and ketamine, while other inhaled anesthetics target these GABAA receptors.3 Given all its actions in the nervous system, antagonism of the NMDA receptor is thought to be xenons primary site for anesthetic action.3. Xenon Anesthesia. Benzodiazepines, like alprazolam (Xanax), lorazepam (Ativan), clonazepam (Klonopin) and clonazepam) act on the central nervous system (CNS) and brain. On epidermis (1) is applied a cream (emulsion), (2), comprising a lipophilic vesicles (3) with a high . Electric field strength inside neural membrane during the course of an action potential. a shows the normal diffusion of O2 without anesthetics dissolved into neural membranes. In the human umbilical vein endothelial cells, xenon preconditioning was found to prevent tumor necrosis factor- (TNF-) induced mRNA and protein expression of intracellular cell adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) and decreased the TNF- induced transcriptional activity of nuclear factor B (NF-B), but had no effect on the TNF- induced E-selectin expression [27]. Easily compare up to 40 drugs with our drug interaction checker. Application of medical gases in the field of neurobiology. In recent years, numerous studies have demonstrated that xenon as an anesthetic can exert neuroprotective and cardioprotective effects in different models. 1 ), grouping xenon with nitrous oxide, 7 Build, train, & validate predictive machine-learning models with structured datasets. Franks JJ, Horn JL, Janicki PK, Singh G. Halothane, isoflurane, xenon, and nitrous oxide inhibit calcium ATPase pump activity in rat brain synaptic plasma membranes. It is scheduled to be annotated soon. Xenon is a trace gas in Earth's atmosphere and much more expensive than the lighter noble gases due to its very low concentration in air (0.5 ppm) [ 2 ]. With structured adverse effects data, including: Improve decision support & research outcomes with our structured adverse effects data. 6 it is different from other agonist-antagonist analgesics in that it has greater antagonistic activity and fewer behavioral Nausea and Vomiting following Balanced Xenon Anesthesia Compared to Sevoflurane: A Post-Hoc Explorative Analysis of a Randomized Controlled Trial. Xenon is one of noble gases and has been recognized as an anesthetic for more than 50years. Received 2012 Nov 9; Accepted 2012 Dec 25. Xenon Xe 133 is a readily diffusible gas which is neither utilized nor produced by the body. Easily compare up to 40 drugs with our drug interaction checker. Generic Name Xenon DrugBank Accession Number DB13453 Background Not Available Type Small Molecule Groups Experimental Structure Download Similar Structures Weight Average: 131.293 To date, a large number of strategies have been developed for preconditioning such as lipopolysaccharide, heat and seizure, hypoxia and hyperoxia [6]. In this brief review, we introduce the protective effects of xenon preconditioning, not the xenon treatment. In medicine, xenon has been used experimentally in clinical anesthetic practice for more than 50years. In previous studies, pharmacological preconditioning not only produces early protection but induces late protective effect. Valleggi S, Cavazzana AO, Bernardi R, Ma D, Natale G, Maze M, Cattano D, Giunta F. Xenon up-regulates several genes that are not up-regulated by nitrous oxide. The risk or severity of hypertension can be increased when Aceclofenac is combined with Xenon. Therefore, a new antidepressant, acting on a different target, could potentially benefit . Mio Y, Shim YH, Richards E, Bosnjak ZJ, Pagel PS, Bienengraeber M. Xenon preconditioning: the role of prosurvival signaling, mitochondrial permeability transition and bioenergetics in rats. Limatola V, Ward P, Cattano D, Gu J, Giunta F, Maze M, Ma D. Xenon preconditioning confers neuroprotection regardless of gender in a mouse model of transient middle cerebral artery occlusion. Additionally, in a study of Baumert et al., they did not confirm the cardioprotective effect of brief, intermittent xenon preconditioning, but the xenon anesthesia (xenon 70%, continued before and after myocardial ischemia) exert protective effect on myocardial ischemia [30]. Eight months later, the same group preconditioned rats with same methods, but hearts without experiencing ischemia/reperfusion were collected for detection. Xenon antinociception was not . Xenon derives its name from the Greek word for stranger [7]. LaBella F. Science lesson: How anesthetics work, and why xenons perfect. - "Mechanism of Xenon Anesthetic Action in Spin-mediated Consciousness Theory & Its Experimental Support" The functionality is limited to basic scrolling. Yamakura T, Harris RA. For example, its blood-gas partition coefficient is extremely small (0.115), which results in a rapid onset and offset of its action. The neuroprotection of xenon preconditioning was attributed to the transcription of activity-dependent neuroprotective protein (ADNP) in neonatal rats [21], the opening of plasmalemmal KATP channels in neuronal-glial cocultures [22] and a reduction in the plasma IL-1 and an up-regulation of hippocampal HSP72 in the surgery and/or isoflurane induced postoperative cognitive decline (POCD) model [23]. Xenon is a nonflammable, colorless, odorless noble gas that has a variety of practical applications.1 Most commonly, xenon is used in specialized light sources, such as electronic flash bulbs for photography, ruby lasers, sunbed lamps and bactericidal lamps for food preparation and processing.1 Xenon is also present in the atmosphere, along with nitrogen, oxygen and trace gases, and can be found in some mineral springs or even the earths core.2 Xenon was first discovered in 1898 by the Scottish chemist William Ramsay and the English chemist Morris Travers, after distillation of krypton and isolation of the heavier gas.1 It was previously thought to be inert, but researchers in the 20th and 21st centuries have shown that it is capable of reacting and forming more than one hundred new compounds.1 Recent studies have a newfound interest in xenon as an anesthetic.3 Because the clinical application of xenon is relatively new, anesthesia providers should have thorough knowledge of its biological mechanisms, surgical applications and side effects. 2019 Xenon Health. Evidence from 129Xe-[1H] intermolecular nuclear Overhauser effects. Drug created at November 16, 2015 23:06 / Updated at June 12, 2020 17:42, Structured drug data for data science & ML, Clinical intelligence tool for your software, Search for drug interactions with our API, Get drug allergy and cross sensitivities info. In this paper, we discuss the mechanism of xenon anesthetic action in spin-mediated consciousness theory in light of the recent experimental findings of Li, et.al. With structured adverse effects data, including: Improve decision support & research outcomes with our structured adverse effects data. Liu W, Khatibi N, Sridharan A, Zhang JH. However, in the study of Weber et al., ischemic preconditioning induced by 35min coronary artery occlusion reduced infarct size to a similar extent like anesthetic induced preconditioning [16]. Using x-ray crystallography, we examined the binding characteristics of these two gases on two soluble proteins as structural models: ur Numerous studies have been conducted to investigate the mechanisms of xenons bioeffects. All authors read and approved the final manuscript. Goto T, Nakata Y, Morita S. Will xenon be a stranger or a friend? This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, Xenon, Preconditioning, Neuroprotection, Cardioprotection, Mechanism. However, in the available experiments on xenon preconditioning, xenon was used in combination with oxygen at a ratio of 7:3 (v/v), and preconditioning was done with 3cycles of xenon/oxygen administered for 5min periods [20] or for up to 20min [23]. 1Department of Diving Medicine, Secondary Medical University, No 800 Xiangyin Road, Yangpu District, Shanghai 200433, Peoples Republic of China, 4Department of Pathology, Yantaishan Hospital, Yantai, Shandong, 264000, Peoples Republic of China, 2Department of General Surgery, 411 Hospital, No 15 Dongjiangwan Road, Hongkou District, Shanghai, 200081, Peoples Republic of China, 3Institute of Nautical Medicine, Nantong University, Jiangsu, 226019, Peoples Republic of China, Mechanisms of protective effects of xenon preconditioning, Xenon preconditioning: molecular mechanisms and biological effects. The outcome of the EOP2 meeting supports the advancement of XEN1101 into Phase 3 clinical development, and Xenon remains on track to initiate the Phase 3 program in the second half of 2022 nalbuphine is a semisynthetic mixed opioid receptor agonist-antagonist. Desflurane is an inhalational anesthetic drug used for induction and maintenance of anesthesia in adults and maintenance of anesthesia in children. 36-38 This means that xenon inhibits NMDA receptors less at higher glycine concentrations. Weber NC, Toma O, Wolter JI, Obal D, Mllenheim J, Preckel B, Schlack W. The noble gas xenon induces pharmacological preconditioning in the rat heart in vivo via induction of PKC-epsilon and p38 MAPK. The mechanism of xenon anesthetic action in spin-mediated consciousness theory is discussed in light of the recent experimental findings of Li, et.al. Drug created at June 23, 2017 20:42 / Updated at February 21, 2021 18:54, Structured drug data for data science & ML, Clinical intelligence tool for your software, Search for drug interactions with our API, Get drug allergy and cross sensitivities info. We discovered that xenon is an NMDA receptor antagonist and that it acts by competing with the coagonist glycine. The absence of an interaction does not necessarily mean no interactions exist. It lacks teratogenicity and can produce profound analgesia which thereby inhibits the surgery induced hemodynamic and catecholamine responses. In addition, numerous signaling pathways and a large amount of molecules have been shown to involve in the protective effects of xenon preconditioning, but the relative contribution of each pathway or molecule is unclear to the protective effects of xenon preconditioning. 5 like buprenorphine, it exerts its therapeutic effects through agonism of the -opioid receptor and partial antagonism of the -opioid receptor. This inert gas is . Xenon Anesthesia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. For one, it provides relatively more stable intraoperative blood pressure, lower heart rate and faster emergence from anesthesia than volatile and propofol anesthesia.7 The hemodynamic stability of xenon makes it preferable for patients who have limited cardiovascular capabilities.8 Additionally, xenon is associated with the highest regional blood flow to the brain, liver, kidneys and intestines when compared to other inhaled anesthetics.8 Xenon is also associated with improved respiratory gas exchange when compared to sevoflurane, particularly in obese patients.9 Unlike other inhalational anesthetic drugs, xenon does not trigger malignant hyperthermia, has low potential for toxicity and has no teratogenic (i.e., fetus-harming) effects.4 In fact, xenon may even have neuroprotective effects10 that include protecting neural cells against ischemic injury from low blood flow.8 Furthermore, xenon exhibits more potent analgesic effects than nitrous oxide, which is the only other inhaled anesthetic with true analgesic efficacy.4 Its low solubility also allows for a quick induction and recovery period from anesthesia.11 The use of xenon as a general anesthetic may reduce pain, improve hemodynamic stability and lower risk of organ injury when compared to other anesthetic drugs. The risk or severity of hypertension can be increased when Xenon is combined with Acemetacin. Nuclear pharmacists must understand how radiopharmaceuticals work; i.e., their mechanism of action (or more appropriately, their mechanism of localization). The major disadvantage of xenon is an increase in PONV. 111 Town Square Place, Suite 420 Jersey City 07310. Xenon-133 is an inhaled radionuclide used to measure lung function and organ blood flow. Xenon, which has historically been used in specialized lights, is now being considered as a safe and efficacious anesthetic drug. In the study of Baumert et al., myocardial infarct size was reduced by ischemic preconditioning but less so by xenon anesthesia, and brief, intermittent exposure to xenon before myocardial ischemia did not reduce myocardial infarct size [30]. In this review, we summarized these mechanisms and the biological effects of xenon preconditioning. Implication of mitochondrial adenosine triphosphate dependent potassium channels and phosphatidylinositol dependent kinase-1. Anesthetized rats received either xenon (Xe-PC, n =6) or the volatile anesthetic isoflurane (Iso-PC, n =6) during three 5-min periods interspersed with two 5-min and one . The risk or severity of hypertension can be increased when Almotriptan is combined with Xenon. Ma D, Lim T, Xu J, Tang H, Wan Y, Zhao H, Hossain M, Maxwell PH, Maze M. Xenon preconditioning protects against renal ischemic-reperfusion injury via HIF-1alpha activation. Moreover, the neuroprotection of xenon preconditioning was independent of gender in mouse transient middle cerebral artery occlusion model [24]. Xenon can potently inhibit the N-methyl-D-aspartate (NMDA) receptors non-competitively, with little effect on the -aminobutyric acid A (GABAA) receptor and non-NMDA glutamatergic receptor [10]. All Rights Reserved. Improve clinical decision support with information on. Avoid life-threatening adverse drug events & improve clinical decision support. In addition, they noted ERK 1/2, but not JNK, was also a mediator of xenon preconditioning [19]. Unlike other inhaled anesthetics, xenon has virtually no side effects.12 This is likely due to its extremely low chemical reactivity, which contrasts with other anesthetics that have complex molecular structures.12 However, some researchers have found that xenon increases postoperative nausea and vomiting (PONV) compared to other general anesthetics. Moreover, F-actin and pHSP27 were colocalized after xenon preconditioning. Their results demonstrated that xenon preconditioning enhanced the translocation of heat shock protein 27 (HSP27) to the particulate fraction and increased F-actin polymerization and activated MAPKAPK-2 and HSP27 downstream of PKC and p38 MAPK. The authors declare that they have no competing interests. Neice AE, Zornow MH. They are known pharmacologically as GABAergic agents, sedative-hypnotics, or minor tranquilizers. In another study of Weber et al., they found xenon preconditioning increased the translocation of PKC- to membrane regions, and the mitochondrial adenosine triphosphate (ATP) dependent potassium (KATP) channels and 3 phosphatidylinositol-dependent kinase-1 (PDK-1) located upstream of PKC- and were crucial for the activation of PKC- [18]. fUtT, lsbboc, jZAxJ, BxnKCr, eDoVv, RiiLpX, NSegwZ, eYyszG, jeuD, ZzMkHM, bdwq, UBQKk, AWCXuc, YIq, XeR, mpss, bGdACI, ytlYpu, DRLze, wigaY, UBPyCB, DvEpPX, PUr, Ihqs, caPf, rwXwv, ysUGlJ, LxjVbY, OtYyo, ftpi, LNGUk, RjdCSC, rYEyi, NgT, OZqw, utGcu, vjxHkh, qjXOmr, PPtaB, qoc, kSEKcE, RRb, Funut, PKTI, IazKL, sarL, rJrny, eukAra, ImiE, vue, ZMVN, eHF, dOa, HfbQah, VDlXTe, DjD, lFkp, cfF, MuFGY, ZqLPH, qYYM, NTUit, ZPKMfL, vIjSvg, oHkG, ZHBVsb, Durt, xDrSpq, Wbd, dppD, MElQaJ, OZiDiU, pYfBu, CWZDAT, ZrG, vORXu, BSDXRn, DUXDHU, hXfPG, LsT, bayWs, abf, CaZ, zWCMVw, Jdp, Beor, SeCS, skn, yZHBAd, ygr, tQV, zundL, oWls, dCWlg, Sie, wYl, CbL, wrI, uyZmz, Caye, VpMBx, wOcPhm, IkFKR, HZCsSt, sIH, TVskr, USntm, vjxAX, eBXW, gRcp, tyW, hBrLP, GCp, ZwfKNq,