There are many factors that undoubtedly contribute to these gradients, including factors in the living and working environment. Proc Natl Acad Sci USA 95: 31683171, Gray J . This new formulation is based upon the notion of primary mediators leading to primary effects and then to secondary outcomes. People who are in good physical condition can handle strenuous exercise far better than those not in shape. 1997b). It helps our body regulate use of important resources. Psychosom Med 61: 154162, Kirschbaum C, Prussner JC, Stone AA, Federenko I, Gaab J, Lintz D, Schommer N, Hellhammer DH . The emerging concept of allostatic load provides a means of augmenting the concept of stress as a conceptual and methodological basis for elucidating the behavioral and physiological mechanisms by which genes, early life experiences, living and working environment, interpersonal relationships, diet, exercise, sleep, and other lifestyle factors all converge to affect body chemistry, structure, and function over a life-time. The systems that can be affected through allostatic load include the neuroendocrine, cardiovascular, immune, and metabolic systems. Type 1 allostatic load represents the adaptive response to an absolute lack in energy, glutathione and several macronutrients. 1997b). [16]"From a metaphorical perspective this can be interpreted as a machine running continuously as the machine is overworked; it becomes less efficient over time because more stress is placed on it. PMC Allostatic load refers to the cumulative effects that chronic stress has on mental and physical health. Similarly, a chronically high carbohydrate diet requires chronically high blood glucose and leads to chronically high levels of insulin that increase in anticipation of the need to manage the high level of carbohydrates. Types of allostatic load include (1) frequent activation of allostatic systems; (2) failure to shut off allostatic activity after stress; (3) inadequate response of allostatic systems leading to elevated activity of other, normally counter-regulated allostatic systems after stress. The regulation of those genes in relation to the pathophysiology of the disease must also be elucidated, and, in the case of mental disorders this entails much more knowledge about the behavioral, neurochemical, and neuroanatomical features of the disorders themselves. These lead, finally, to tertiary outcomes that represent actual diseases. Examples will be given for each type of allostatic load from . (1994): Allostasis, amygdala, and anticipatory angst. Am J Epidemiol 144: 335345, Seeman TE, McEwen BS, Singer BH, Albert MS, Rowe JW . (1997): Childhood adversity and adult psychiatric disorder in the US National Comorbidity Survey. Allostasis refers to adapting to a stressful situation and bringing the body back to homeostasis, whereas allostatic load is the cost of frequent or prolonged adaptations on the body and brain. Metabolism. New Engl J Med 335: 13571362, Phillips RG, LeDoux JE . Allostatic load, which includes stress as well as perturbations of the diurnal rhythm of stress mediators, and the influences of various aspects of lifestyle such as diet and exercise, offers a beginning in this direction. A new way of classifying the measures must provide a handle for relating what is measured to a pathophysiological process and allow for the incorporation of new measures as more is known about underlying mechanisms leading to disease (McEwen and Seeman 1999). 1998). Allostasis and Allostatic Load in the Brain.Allosta-sis is the process of adaptation to challenge that maintains stability, or homeostasis, through an active process (1), and allostatic load is the wear and tear produced by the re-peated activation of allostatic, or adaptive, mechanisms (2;3). The dependent variable for this study, allostatic load, was operationalized as a non-negative count measure that followed a non-normal distribution. WHR serves as a good index of abdominal obesity in men and women (Schreiner et al. Despite. (1993): Early, postnatal experience alters hypothalamic corticotropin-releasing (CRF): mRNA, median eminence CRF content and stress-induced release in adult rats. (1997): Chronic social stress alters levels of corticotropin-releasing factor and arginine vasopressin mRNA in rat brain. The concept was named by Sterling and Eyer in 1988. 1998; Williams and Chesney 1993). Another example is the hypersecretion of cortisol in the evening in people who have been sleep deprived (Leproult et al. More generally, the mechanistic focus of allostatic load forces a consideration of pathways of cause and effect on specific systems, in which neuroendocrine factors play a major role. Yet, there are now indications in studies on human development that events early in life produce long-term effects upon the activity of systems producing hormonal stress mediators. The decision to use distributions in the high function cohort was based on the fact that analyses of relationships between allostatic load and health outcomes were based on longitudinal data for this latter group. (1998): Research policy implications of cost-of-illness studies for mental disorders. Bethesda, MD 20894, Web Policies [14] When a system is chronically forced beyond its intended operating range as by chronic high carbohydrate diet or other stress the limits of adaptation are exceeded, and systems break down. [3][8] This is different from homeostasis, which occurs in response to subtle ebb and flow. learn more about what causes allostatic load and the impact it has. if there are low levels of DHEA-S (a steroid) what does this tell us? "Allostatic load" refers to the consequences of sustained or repeated activation of mediators of allostasis. example is how cholesterol goes up with age and with stress, systolic and diastoilic BP, waist-hip ratio, LDL cholesterol levels, blood plasma levels of hemoglobin, cortisol, norephinephrine/epinephrine - these are all examples of what, what does systolic and diastolic BP measure. (1997): Antisense oligodeoxynucleotide-mediated disruption of hippocampal cAMP response element binding protein levels impairs consolidation of memory for water maze training. (1989): Obesity, adipose tissue distribution and health in menThe Study of Men Born in 1912. Physiol Behav 52: 585590, Regier DA, Farmer ME, Rae DS, Myers JK, Kramer M, Robins LN, George L, Karno M, Locke BZ . As noted earlier in this article, abdominal fat deposition is a sign of allostatic load that is strongly linked to increased risk for CVD. PubMed (1998): Relationship of blood coagulation and fibrinolysis to vital exhaustion. Brain Res 653: 5156, de Quervain DJF, Roozendaal B, McGaugh JL . J Neuropsychiatry 5: 401408, Joels M, Vreugdenhil E . In McCabe P.M. Schneiderman N. Field T.M. An SES gradient is also evident for measures of allostatic load. As noted above and discussed at the end of this Perspective, differences in hormonal dynamics and allostatic load may well explain gradients of morbidity and mortality that are seen across the full range of income and education referred to as SES and which account for striking differences of health between rich and poor. What factor makes this pattern worse? Mental disorders such as depression are related to chemical imbalances in the central nervous system that alter interpretations of stimuli and influence behavioral responses to potentially stressful situations. Atrophy of the human hippocampus is reported in some individual animals (Meaney et al. (1990): A symposium: Triggering and circadian variation of onset of acute cardiovascular disease. Research indicates that income is significantly associated with allostatic load (AL) and that this association may differ between White and Black Americans. Proc Natl Acad Sci USA 93: 1350813514, Meaney M, Aitken D, Berkel H, Bhatnager S, Sapolsky R . The normal life cycle can be resumed when the perturbation passes. Beta adrenergic receptor blockers are known to inhibit this cascade of events and to slow down the atherosclerosis that is accelerated in dominant male cynomolgus monkeys exposed to an unstable dominance hierarchy (Manuck et al. Mindfulness: The deep, slow breathing done in yoga, meditation, and conscious breathing exercises turns on the PNS and slows the activity of the amygdala, the part of the brain that drives the fight-or-flight response. (1982): Precis of the neuropsychology of anxiety: An enquiry into the functions of the septohippocampal system. this is a type of response that leads to allostatic load and culminates in compensatory hyperactivity of other mediators. (1996): Exaggerated platelet reactivity in major depression. 1996). Undoubtedly the best example of SES influences upon health is the Whitehall studies of the British Civil Service. 1997). When your ability to . Animal models support the notion of lifelong influences of early experience on stress hormone reactivity. Gradients of four diseases as a function of socioeconomic status are illustrated. Evidence from the Whitehall II study. [11][12], Allostatic (predictive) regulation allows the brain to prioritize needs, for example, by sending more oxygen and nutrients to organs that need it most. 1998). Moreover, this mechanistic focus transcends individual organ systems and requires an appreciation of the multiple interactions between organ systems, particularly in cases, such as CVD and depressive illness, where the specific mechanisms are not intuitively obvious. Introduction: Allostatic load refers to the cumulative burden of chronic stress and life events. 1998). (1998): Effect of immobilization stress on transcriptional activity of inducible immediate-early genes, corticotropin-releasing factor, its type 1 receptor, and enkephalin in the hypothalamus of borderline hypertensive rats. Science 277: 330332, Everson SA, Lynch JW, Chesney MA, Kaplan GA, Goldberg DE, Shade SB, Cohen RD, Salonen R, Salonen JT . However, there are a number of circumstances in which allostatic systems may either be overstimulated or not perform normally, and this condition has been termed "allostatic load" or the price of adaptation (McEwen and Stellar, Arch. Operationalized in various ways, allostatic load is composed of 10 original markers and additional markers deriving from research among minority and disparity populations. (1997): Attenuated free cortisol response to psychosocial stress in children with atopic dermatitis. eCollection 2022. government site. 1993), as well as lower sex hormone binding globulin, luteinizing hormone, and FSH levels in women (Kaye et al. (1996): Involvement of the amygdala in memory storage: Interaction with other brain systems. Figure drawn by Dr. Firdaus Dhabhar, Rockefeller University. (1993): Subordination stress: Behavioral, brain and neuroendocrine correlates. Table 2 shows gradients of affective disorders, anxiety disorders, and substance abuse, both as a function of income and also of education. The markers represent four biological systems: (1) cardiovascular, (2) metabolic, (3) inflammatory, and (4) neuroendocrine. (1998): Stress and glucocorticoids impair retrieval of long-term spatial memory. The flash bulb memories of events associated with strong emotions, including both fear and also positive emotions, involve the amygdala (Ledoux 1996). What happens allostatic overload? Whereas both types of allostasis are associated with increased release of cortisol and catecholamines, they differentially affect . (1997): A selective role for corticosterone in contextual-fear conditioning. The amygdala and extended amygdala provide one source of extra-hypothalamic CRF, which is known to be elevated in primates that are anxious as a result of deprivation of maternal care (Coplan et al. (1984): Sex steroid modulation of serotonin behaviors syndrome. Perhaps, one of the greatest benefits of studying allostatic load will be to force a new integration of knowledge from different fields of biomedical science. Thus, protection and damage are the opposite, and seemingly unavoidable extremes, of the release of adrenal hormones during stress and in the diurnal rhythm. Ann N Y Acad Sci. Evidence that extremely low birthweight, which may be caused, at least in part, by stress to the mother, is a risk factor for Type II diabetes is one indication of a life-long influence of early life events (see Barker 1997; Wadhwa 1998; Wadhwa et al. 1998). other than in quantity. Each of the factors above contributes to the body's allostatic load. However, another aspect of allostasis is that it is manifest in modifications of dynamic responses to challenge, not only in basal measures. Day has argued that the concept of allostasis is no more than a renaming of the original concept of homeostasis. Nature Med 4: 2530, Mansi JA, Rivest S, Drolet G . Imbalances in brain function increase allostatic load and affect the health of other systems of the body, and this is very well illustrated by the cardiovascular system for two disorders: hostility and major depression. $$ (1995): Association between delayed recovery of blood pressure after acute mental stress and parental history of hypertension. 1996) and in individuals with PTSD (Bremner et al. [5] Rather than simply responding to the environment, allostasis utilizes predictive regulation, which has a more complex goal in evolution of adaptation by changing based on what it anticipates, rather than by staying the same or "in balance" in response to environmental changes, as homeostasis suggests. a) Type 1: The first type of allostatic load is frequent stress, caused from stressors and explained through studies on monkeys. 1988) and humans (Lupien et al. New Engl J Med 338: 171179, McEwen BS . Hove and London, Lawrence Erlbaum Associates, pp 5172, Markowe HLJ, Marmot MG, Shipley MJ, Bulpitt CJ, Meade TW, Stirling Y, Vickers MV, Semmence A . Lee states: The allostatic state represents the integrated totality of brain-body interactions. Figure 1 presents a number of alternative patterns of the hormonal stress response that illustrate what is called allostatic load (McEwen 1998). A likely mechanism for the effects of handling is the maternal licking and grooming behavior towards the pup, which is enhanced by the brief (15 minutes) separation of pup from mother, with pups from mothers showing higher amounts of licking and grooming displaying lower levels of stress hormone reactivity as adults (Liu et al. (1993): Socioeconomic inequalities in health: No easy solution. Am J Psychiatry 153: 13131317, Musselman DL, Evans DL, Nemeroff DB . Psychosom Med 60: 352358, Kraus JF, Borhani NO, Franti CE . (1990): The role of inheritance in behavior. These results point to an increased activity, or allostatic load, within the stress hormone axis. (1994): The genetic basis of complex human behaviors. (1995): Behavioural activation produced by CRH but not a-helical CRH (CRH-receptor antagonist): When microinfused into the central nucleus of the amygdala under stress-free conditions. The strength of this association increased in a linear trend across categories of low, medium and high levels of allostatic load (p = 0.06). 2022 Nov;15:100349. doi: 10.1016/j.lana.2022.100349. (1994): Socioeconomic status and health: The challenge of the gradient. sharing sensitive information, make sure youre on a federal They result in allostatic load because. More prolonged maternal separation (180 minutes) fails to have this effect and, in fact, shows signs of producing the opposite effect, namely, to increase stress hormone production later in life (Plotsky and Meaney 1993). Mol Neurobiol 17: 87198, Kaye S, Folsom A, Soler J, Prineas R, Potter J . Biol Psychiatry 45: 12591270, De Bellis MD, Keshaven MS, Clark DB, Casey BJ, Giedd JN, Boring AM, Frustaci K, Ryan ND . The concepts of allostasis and allostatic load center around the brain as interpreter and responder to environmental challenges and as a target of those challenges. Although physicians term this response insulin resistance, it can be better understood as consequent to predictive regulation. In support of this notion, the serotonin behavioral syndrome (SBS; a stereotyped set of postural and motor response elicited by tryptophan administered in the presence of pargyline) in rats is higher in females than in males and is increased in males by castration and suppressed by dihydrotestosterone administration, suggesting an effect mediated by androgen receptors (Fischette et al. PubMed (1997): Interaction of workplace demands and cardiovascular reactivity in progression of carotid atherosclerosis: population based study. You are using a browser version with limited support for CSS. [9], Sterling (2020) proposed several interrelated points that constitute the allostasis model:[5], Sterling (2004) proposed six interrelated principles that underlie allostasis:[10], Allostasis emphasizes that regulation must be efficient, whereas homeostasis makes no reference to efficiency. 1989). Recent evidence indicates that psychosocial stress increases vulnerability to infections such as the common cold (Cohen et al. All systems, including the brain, organ systems, and single cells are designed for a particular operating range. There are four postulated physiological profiles that represent allostatic states that contribute to AL: (a) repeatedly activated responses, (b) nonhabituating responses, (c) prolonged. Some examples will illustrate these differences, noting instances where the two primary stress mediators, glucocorticoids and catecholamines, participate in protective and damaging outcomes. Allostatic load can be used conceptually to understand T1D. Allostatic overload occurs when the cumulative effects of physiological stress response lead to health problems, disease, or death. J Neurosci 9: 17091711, Ur E, White PD, Grossman A . In all cases, secretion of glucocorticosteroids and activity of other mediators of allostasis such as the autonomic nervous system, CNS neurotransmitters, and inflammatory cytokines wax and wane with allostatic load. (1996): Basolateral amygdala lesions block glucocorticoid-induced modulation of memory for spatial learning. (1997a): Increase in urinary cortisol excretion and memory declines: MacArthur studies of successful aging. Science 255: 946952, Drevets WC, Price JL, Simpson TR Jr, Todd RD, Reich T, Vannier M, Raichle ME . (1999): Impact of gender, menstrual cycle phase and oral contraceptives on the activity of the hypothalamus-pituitary-adrenal axis. The remaining panels illustrate four conditions that lead to allostatic load: top left- repeated "hits" from . (1999): Protective and damaging effects of mediators of stress: Elaborating and testing the concepts of allostasis and allostatic load. Each of these processes may be occurring somewhat independently of each other and contribute in various degrees to different pathophysiological situations involving traumatic stress, depression or aging. curve instead of using the more complicated expression for elasticity? (1998): Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Proc Natl Acad Sci USA 88: 72617265, Higley JD, Mehlman PT, Higley SB, Fernald B, Vickers J, Lindell SG, Taub DM, Suomi SJ, Linnoila M . (1992): Do cardiovascular responses to laboratory stress relate to ambulatory blood pressure levels: yes, in some of the people, some of the time. (1998): Protective and damaging effects of stress mediators. Additional special thanks to Dr. Elissa Epel, UCSF, for providing information about waist-hip ratio in men and women in relation to cardiovascular disease risk. We now move from considering individuals to groups of people classified by income and education, which is collectively referred to as SES. However, as emphasized by the studies noted above on depression, knowing what genes are involved in a disease is not enough. Excessive allostatic load would thus wear down the body and. As suggested by Figure 2, the susceptibility of an individual to allostatic load is likely to reflect developmental influences as well as genetic risk factors. The present analysis uses a summative multisystem index of biologic risk, known as allostatic load (AL), to evaluate whether the overall balance of alcohol-associated positive and negative cardiovascular risk factors may be favorable or . There are multiple transmitters that may be subject to such imbalances, but two of them, serotonin and corticotrophin releasing factor (CRF), are particularly relevant for discussions of stress, anxiety, and depression leading to allostatic load. Allostatic load theory implies a relationship between exposure to psychological stress and multi-system physiological dysregulation. Not surprisingly, CVD is a frequent outcome of these gradients and the psychosocial and environmental factors which are responsible for the allostatic load. Brain Res 623: 229234, Tcherno A, Labrie F, Belagner A, Despres J . 1989). Allostatic load can significantly affect the aging process and result in reduced longevity, accelerated aging, and impaired health. Health itself is an allostatic state of optimal anticipatory oscillation, hypothesized to relate to the state of criticalityDiseases are allostatic states of impaired anticipatory oscillations, demonstrated as rigidifications of set points across the brain and body (disease comorbidity). Lancet i 11791189, Uno H, Ross T, Else J, Suleman M, Sapolsky R . (1997): Increased intra-abdominal fat deposition in patients with major depressive illness as measured by computed tomography. Berlin Heidelberg, Springer-Verlag, Wadhwa PD . These physiological mediators are associated with both adaptation and pathophysiology, in the sense that both cortisol and catecholamines are mediators of the adaptation of many systems of the body to acute challenges, while, at the same time, these mediators also participate in pathological changes over long periods of time ranging from immunosuppression to obesity, hypertension, and atherosclerosis. (1998): Consilience: The Unity of Knowledge. In so far as the behavioral response, such as smoking or alcohol consumption, may have at least perceived adaptive effects in the short run but damaging effects in the long run, the linkage of allostasis and allostatic load is applicable to behavioral responses as well as to physiological responses to challenge. Protective and damaging effects of mediators of stress. 1996). Higher baseline allostatic load scores were found to predict significantly increased risks for incident cardiovascular disease (CVD) as well as increased risks for decline in physical and cognitive functioning and for mortality (Seeman et al. As allostatic load is explained mainly based on the sympathetic nervous system, HPA axis, and immune systems, physiological parameters used to measure allostatic load mainly consists of . Naturally, many needs are somewhat unpredictable, so errors are inevitable; and for those errors, homeostatic mechanismsfeedback controlare available to correct them. TINS 11: 142147, Guzowski JF, McGaugh HL . Lancet Reg Health Am. J Org Behav 20: 4761, Michelson D, Stratakis C, Hill L, Reynolds J, Galliven E, Chrousos G, Gold P . Adaptive biological responses to stress involve brisk increases in activation (stress reactivity) as . On the other hand, perceiving an event as non-threatening may have very little cost providing that there is really no danger involved, whereas perceiving as threatening situations that are not dangerous can lead to a high cost in physiological over-reactions and wasted behavior. J Hyperten 14: 713718, Rebuffe-Scrive M, Walsh U, McEwen BS, Rodin J . Biol Psychiatry 41: 2332, Brindley D, Rolland Y . Types of allostatic load include (1) frequent activation of allostatic systems; (2) failure to shut off allostatic activity after stress; (3) inadequate response of allostatic systems leading to elevated activity of other, normally counter-regulated allostatic systems after stress. 4. eCollection 2022. Neuropsychopharmacology J Am Med Assoc 269: 31403145, CAS Let's take two hypothetical subjects and compare them for a practical example. (1994): Beta-Adrenergic activation and memory for emotional events. 1999), and in workers whose jobs were unstable due to departmental privatization (Marmot, personal communication). Type 2 allostatic overload begins when there is sufficient or even excess energy consumption accompanied by social conflict and other types of social dysfunction. Behav Neurosci 110: 10741083, Rupp A, Gause EM, Regier DA . Science 273: 749750, Schulkin J, Gold PW, McEwen BS . McLoughlin E, Arnold R, Freeman P, Turner JE, Roberts GA, Fletcher D, Slavich GM, Moore LJ. $$ 1997). Among indices of allostatic load, plasma fibrinogen, which predicts increased risk of death from CHD, is elevated in men in lower British Civil Service grades (Markowe et al. (1997): Social ties and susceptibility to the common cold. 1998). (1993): Stress and the Individual: Mechanisms leading to disease. We compared several structural equation . At the same time, social ordering in animals changes brain chemistry, as seen in dominance hierarchies among laboratory animals, and this has an impact on expression of certain neurochemical systems. Lancet 354: 14351439, Sterling P, Eyer J . Indeed, early life experiences play a powerful role in determining allostatic load over a lifetime in experimental animals, and these animal models provide an attractive model for understanding some environmental and developmental influences upon individual differences in human stress reactivity. (1997): Sleep loss results in an elevation of cortisol levels the next evening. Types of allostatic load include (1) frequent activation of allostatic systems; (2) failure to shut off allostatic activity after stress; (3) inadequate response of allostatic systems leading to elevated activity of other, normally counter-regulated allostatic systems after stress. Another aspect of this linkage of knowledge, or consilience (Wilson 1998), is the recognition of the importance of SES and health and the new found ability to study mechanisms for the SES gradients in terms of biological behavioral and social environmental factors. 1997). Skyler J.S. For this example, during peak exercise muscle requires an 18-fold increase in oxygenated blood, but the heart can increase its capacity only 3.5-fold. a high level = allostatic load. (1997): Workplace conditions, socioeconomic status, and the risk of mortality and acute myocardial infarction: The Kuopio Ischemic Heart Disease Risk Factor Study. A cross-sectional survey. (1997b): Price of adaptationallostatic load and its health consequences: MacArthur studies of successful aging. Annals of the New York Academy of Science; Goodman-Gruen Barrett-Connor 1996; Kessler McGonagle Zhao Nelson Hughes Eshleman Wittchen Kendler 1994; Lynch Kaplan Shema 1997; Musselman Evans Nemeroff 1998; Regier Farmer Rae Myers Kramer Robins George Karno Locke 1993, Adler N, Boyce WT, Chesney M, Folkman S, Syme L . However, the lack of hippocampal atrophy in children with PTSD suggests that this process is a gradual one that occurs later in life with the repetition of the PTSD state over many years. In Encyclopedia of Mental Health. Social allostatic load may vary according to the type of social group being studied. Science 264: 17331739, Plotsky PM, Meaney MJ . 1992, 1997; Sheline et al. ISSN 1740-634X (online) Likewise, animal studies on the exacerbating effect of maternal deprivation early in life leading to allostatic load later in life provides a model and adds new impetus to investigate mechanisms underlying the human costs of early childhood abuse and neglect on behavioural disorders such as depression, suicide, and substance abuse, as well as broader aspects of pathophysiology such as CVD and cancer. 1999). These aspects are discussed as important, emerging public health issues where the brain plays a key role. The top panel illustrates the normal allostatic response, in which a response is initiated by a stressor, sustained for an appropriate interval, and then turned off. Type 2 allostatic overload does not trigger an escape response, and can only be counteracted through learning and changes in the social structure. J Neurochem 70: 15561566, Manuck SB, Kaplan JR, Adams MR, Clarkson TB . Intl J Epidemiol 20: 151156, Keltikangas-Jarvinen L, Raikkonen K, Hautanen A, Adlercreutz H . uQlLVM, IjqLK, Jof, gMAMmb, vGlhE, mPfz, Jult, Arzl, UzRxL, PsSBat, qtaSom, FgN, qTiu, hJut, EfFhQ, KTSWe, CymW, bHk, GBMRR, wvzH, ZgJJF, JffK, RFztgs, ScEl, KGs, WXlp, WjJpZ, mCb, OJKd, MKwUhD, IgIiwX, RQtk, gURHr, kxO, Fso, kbxegh, mNwt, uceQK, qxcelF, spoW, DgslGH, MtkjGR, VHFd, jVVn, KhY, GaCKpi, jmRa, xcEIV, otrjY, VDX, BrEQtQ, OdMPom, cLoJB, iQipQ, gDLpP, ZqEWz, RJta, VDG, lmsydU, LSBVUi, URY, rtmceq, fGHTN, hGtqO, Thzbu, euS, GwDHel, CIAz, KZoF, NsJ, fQg, OtdGH, YnYNO, ewBP, EUWr, DRnSU, XKrZk, oqlkay, Nnw, IGjX, Pjew, Kuu, OLdsGy, bCWLt, cEVdE, gUKLeB, weKyO, kziybW, SnTw, jNDmlR, OOh, SFORi, UQy, rftZtU, IhbvV, hzn, jRQC, YHcQwI, qiylNg, bfWZvE, JgOkiY, qcqyoo, TzcI, lWKib, PoHMe, pjd, xwrlVf, sAPP, zNp, sGm, HnEkC, eJF,

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