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Clin Exp Immunol. Apr 1999; 116(1): 19–27.
PMCID: PMC1905230

Vitamin D, thyroid hormones and muscle mass influence natural killer (NK) innate immunity in healthy nonagenarians and centenarians


Increasing evidence has demonstrated that the immune system closely interacts with other physiological systems, whose communications are mediated by circulating cytokines and hormones. The aim of our study was to test whether the number and cytolytic activity of NK cells in a group of relatively healthy Italian nonagenarians and centenarians were affected by the modifications of endocrine, metabolic and functional parameters that occur during ageing. Because of the extreme age of the study population, a cross-sectional analysis was performed. This study revealed that the group of oldest subjects with the highest number of NK cells and the best preserved cytolytic function also presented a preserved metabolism of thyroid hormones and vitamin D and integrity of muscle mass. In fact, the NK cell number and/or cytolytic activity of healthy subjects > 90 years old was positively associated with serum levels of vitamin D, while T3, FT4, i-PTH hormones and lean body mass were associated only with NK cell number. In conclusion, our results stress the paramount importance of nutritional evaluation in the clinical assessment of elderly people.

Keywords: immune response, ageing, thyroid hormones, vitamin D, muscle mass


NK cells are a distinct subpopulation of lymphocytes identified by CD16 and CD56 antigens, that display a spontaneous cytolytic activity against various types of tumour or infected cells. NK cells may therefore play an important role in early natural surveillance against infections and malignant transformations [1].

Since advancing age in humans has been associated with increased morbidity and mortality for neoplastic and infectious disease and with an impairment of immune function [2, 3], several groups have investigated the impact of ageing on the mechanisms and surface structures involved in NK cell activation and function [46]. The most prominent finding is the progressive increase in the number of circulating NK cells with age, associated with a decreased cytolytic activity of sorted NK cells or of cloned NK cell precursors [79].

In addition, some environmental influences have been reported: cigarette smoking was reported to decrease NK cell number and activity [10, 11], while contradictory results were obtained on the influence of regular alcohol consumption [12, 13] on the immune system.

Most of these studies, however, were carried out on elderly populations with a relatively young age range [1416] and investigated NK activity in relation to a limited number of biological parameters [5, 6, 17] more or less in isolation from each other. Other investigations were performed on cohorts with different racial characteristics and living habits (such as Japanese subjects) [18], very different from north-western populations.

In recent years increasing evidence has demonstrated that the immune system closely interacts with other physiological systems, whose communications are mediated by circulating humoral factors such cytokines, hormones and neurotransmitters that influence each other through sensitive receptors distributed to various target tissues in the body [1921]. It is well known that hormones of the hypophysis [22], thyroid [23], adrenals [24], gonads [2527] and the calcium-regulating hormone 1,25-dihydroxyvitamin D3 [28] affect the homeostasis of the immune system, with a direct action on immunocompetent cells. In addition, endocrine hormones regulate cellular respiration and many aspects of carbohydrate, fat, and amino acid metabolism, so affecting energy metabolism and the overall immune system function.

The biological bases of endocrine changes with ageing are well established [29]: impairment of thyroid, gonadal and adrenal function, decline in growth hormone secretion with decreased insulin-like growth factor levels and a reduction in both exogenous intake and endogenous synthesis of vitamin D. These hormonal systems play an important role in maintaining the integrity of muscle and bone mass and together with malnutrition and deficit of vitamins and trace elements are a critical determinant of immunocompetence in the elderly [30, 31]. In addition, many other factors such as lifestyle, the use of drugs and functional status defined as physical mobility, mental alertness and self satisfaction can also be important in immune and metabolic modifications found in the elderly [32].

The aim of our study was to test whether the number and cytolytic activity of NK cells in a group of relatively healthy Italian nonagenarians and centenarians were affected by the modifications of endocrine, metabolic and functional parameters that occur during ageing. Because of the extreme age of the study population, a cross-sectional analysis was performed.



Sixty-two elderly subjects 90–106 years old (mean age ± s.d. 97 ± 3 years), 37 women and 25 men, were enrolled in the present study, following the suggestions of the Senieur protocol admission criteria for immunogerontological studies in man [33]. They were relatively healthy with respect to the general elderly population and independently living in their own homes. None was taking drugs or supplements known to affect the immune system and chronic illness was excluded by serum C-reactive protein (CRP) quantification (Beckman, Galway, Ireland).

Subjects gave their informed consent to enrol in the present study, which was approved by the local ethical committee.

Peripheral blood samples, collected at home by one investigator from 8–9 a.m. from overnight fasting subjects, underwent biochemical and immunological determinations.

To minimize the influence of circadian variation, samples from all subjects were collected twice a week on the same days and from three to five samples were analysed together.

Hormone measurements

Circulating levels of triiodothyronine (T3), thyroxine (T4), free-T3 (FT3), free-T4 (FT4), thyrotropin stimulating hormone (TSH), growth hormone (GH), 17-β-estradio1 (E2) were assayed in serum by commercial Fluoroimmunoenzymatic Kits (Eurogenetics, Tessenderlo, Belgium)

Cortisol (Immunotech, Marseille, France), dehydroepiandrosterone sulphate (DHEAS; Radim, Pomezia, Italy), free testosterone (FT; Diagnostic System Labs, Webster, TX) and dihydrotestosterone (DHT; BioMerieux Vitek, Hazelwood, MO) were assayed in serum by commercial radioimmunoassay (RIA) kits, while insulin-like-growth factor 1 (IGF-1) (Diagnostic System Labs) and intact parathyroid hormone (i-PTH; (Radim) were assayed by IRMA kits and 1,25(OH2)D3 by radioreceptorial assay (Incstar, Stillwater, MN).

Mononuclear cell preparation and flow cytometry analysis

Mononuclear cells were separated by conventional density gradient centrifugation and stained with CD3, CD16 and/or CD56 FITC or PE MoAbs from Becton Dickinson (Mountain View, CA) in V-bottomed plates for 30 min at 4°C, washed with PBS–fetal calf serum (FCS) and resuspended in 1% paraformaldehyde. The analysis was performed by cytometry with a FACStar Plus cell sorter from Becton Dickinson [7].

NK cell lytic activity

K562 tumour target cells (2 × 106) were incubated with 100 μCi of radioactive sodium chromate from NEN (Bad Homburg, Germany) (specific activity 400–1200 Ci/g). 51Cr-labelled target cells (5 × 102/50 μl) and a varying number of effector cells (from 5 × 104 to 5 × 102/100 μ1) were incubated in triplicate in V-bottomed 96-well plates for 4 h. Then 75 μl of supernatant were harvested and 51Cr release was calculated as: (experimental release — spontaneous release)/(maximum release — spontaneous release) × 100. Spontaneous release (obtained by target cells alone) was as high as 10% of maximum release (obtained by target cells lysed with 1% Triton X-100) [34]. A group of five subjects was tested subsequently to define day to day variability in NK activity (without observing significant differences).

Anthropometric assessment

Nutritional status was assessed by serum albumin determination (Boehringer Mannheim Biochemica, Mannheim, Germany) and anthropometric evaluations. The upper limb [35] arm muscle area (AMA) and arm fat area (AFA) were derived from measurements of mid-arm circumference and triceps skinfold thickness (TST) [36]. TST and AFA reflect body fat mass (calorie reserves), AMA reflects muscle mass (proteins). The measurements were taken by the same investigator on all the subjects.

Functional assessment

Katz's Activities of Daily Living (ADL) scale [37] was used as a functional capacity index. The ADL score summarizes the profile of the person's overall level of disability as measured in six basic functions (bathing, dressing, going to the bathroom, transferring from bed to chair, continence and eating). The original classification from A to F was transformed to a numerical score from 1 (independent in all functions) to 7 (dependent in all functions).

Symptoms of depression were investigated using the Geriatric Depression Scale (GDS) [38], a psychological questionnaire avoiding physical complaints. Scores below 11 indicate absence of depression, between 11 and 20 mild depression, above 20 severe depression.

An Italian version of Folstein's Mini Mental State Examination (MMSE) [39] was used as a general measure of cognitive function. The MMSE consists of 20 separate items which add up to a maximum score of 30. Generally a score ≤ 23 indicates cognitive impairment.

Lifestyle factors including cigarette smoking (defined as being ex-smoker, no smoker, or current smoker), and current alcohol consumption (because of the peculiar features of this very old population, dichotomized as ‘drinking’ or ‘not drinking wine at meals’) were recorded.

Statistical analysis

The experimental data were expressed as means ± s.d. Analysis was performed using the following tests: Kolmogorov–Smirnof for normality of distribution followed by logarithmic transformation for skewed distributed values; Student's t-test or Mann–Whitney U-test for statistical significance between means depending on the normal distribution of values or not; Pearson's correlation coefficient, Spearman's R and Kendall's τ for relations among variables; χ2 test for associations. Principal component analysis and multivariate analysis of variance were also performed.

The SPSS for Windows package was used to perform statistical analysis.


NK cells showed a similar functional cytolytic activity in elderly men and women (Fig. 1a) together with a similar wide distribution in the peripheral blood where NK cells accounted for 5–40% of total lymphocytes (Fig. 1b).

Fig 1
Functional activity of NK cells and phenotypical distribution of CD16 and CD56 lymphocytes in the peripheral blood of elderly subjects. (a) Results are expressed as mean percentages of 51Cr release ± s.e.m. of women (•) and men (○). ...

CD16 cell number showed a direct linear relation to CD56+ cells but an inverse one to CD3 cell number (Fig. 2a). CD3+ cell number was similar in males and females (61 ± 2, mean percentages ± s.e.m.) and decreased as a function of age (Pearson's coefficient r =−0.32, P < 0.05) (not shown).

Fig 2
Multiple scatterplot between T and NK lymphocytes and between NK lymphocytes and cytolytic activity. (a) A direct correlation was found between CD16 and CD56 cell numbers (• and continuous line) (Pearson's coefficient r = 0.64, P < 0.001), ...

CD16 cell number was also related to cytolytic activity for all the different effector:target cell ratios from 100:1 to 1:1 (P < 0.05 at least).

The best fit between CD16 cell number and cytolytic activity obtained for the different effector:target cell ratios was found for 100:1 ratio, following a quadratic model, where the lowest residual variance was obtained, using the equation: E/T100 = (4.48 (%CD16) − 0.09 (%CD16)2), where E/T100 corresponds to the percentage of 51Cr release obtained from 100:1 effector:target cell ratio (Fig. 2b). Hence the 100:1 cell ratio was chosen for the subsequent statistical analyses.

The enhanced cytolytic activity was evident from the increase in CD16+ cells up to 30%; beyond this percentage (Fig. 2b) cytolytic activity tended to decrease but not significantly.

A trend toward decreased NK cell numbers and cytolytic activity was found in alcohol drinkers, but it failed to reach significance, while a significant decreased cytolytic activity was found in cigarette smokers (Kendall's τ coefficient r = −0.35, P < 0.01) (mean percentage 51Cr release for 100:1 effector:target cell ratio ± s.e.m. for non-smokers 47.7 ± 3, and for ex-smokers 26.9 ± 7, t-test P < 0.01). The habits of drinking and smoking were also associated in lifestyle (Kendall's τ coefficient r = 0.341, P < 0.05).

None of the subjects suffered from chronic illness as determined by serum CRP quantification (males 0.43 ± 0.18 mg/100 ml, females 0.43 ± 0.16 mg/100 ml, normal values < 0.8 mg/100 ml).

Serum concentrations of endocrine hormones in the studied subjects are shown in Table 1. As shown, several subjects had hormonal values below the normal range for young adults. However, reduced hormonal levels in advanced age do not necessarily imply an underlying endocrine disease since there is a physiologic age-related decline in the secretion of thyroid hormones, gonadal and adrenal sex steroids and vitamin D, whereas PTH levels tend to increase and cortisol levels remain unchanged [29].

Table 1
Serum concentrations of endocrine hormones in the study subjects

It is commonly accepted that some hormones present a circadian rhythm which is modified during ageing, not as daily kinetics but as range intervals. To avoid modifications due to circadian rhythm, all the samples for our study were collected in the same time interval in the morning.

FT and DHT were measured in men only, because the age-related changes in testicular secretion occur over a longer period of time and are more gradual than in the female gonad. The adrenal androgen DHEAS and the oestrogen E2 were instead measured in both sexes, since the adrenal cortex represents the main source of sexual steroids for post-menopausal women and in aged men small but significant amounts of oestrogens are still produced through the peripheral conversion of androgen precursors.

Only T3 and FT4 levels were directly correlated with NK cell number (Fig. 3), without differences between men and women for T3, but with an evident influence of women for FT4 (Pearson's coefficient r = 0.39, P < 0.02) (not shown), while no correlation was observed for these two hormones with cytolytic activity or with age. Only FT4 maintained its positive relation with CD16 (R2 = 0.84, s.e.m. = 7.7, P < 0.001) following regression analysis.

Fig 3
Multiple scatterplot between NK lymphocytes and thyroid hormones. CD16 cell numbers were directly correlated with T3 (Pearson's coefficient r = 0.28, P < 0.05) (• and continuous line) and FT4 (Pearson's coefficient r = 0.34, P < ...

No correlation with NK cell number and cytolytic activity was found among cortisol, DHEAS and estradiol in both sexes, and similarly for FT measured only in men. On the contrary, the active form of testosterone (DHT) (Fig. 4) was correlated with NK cell number (regression analysis R2 = 0.74, s.e.m. = 9.7, P < 0.001). In addition, decreased DHEAS was correlated with decreased physical ability (Spearman's coefficient r = 0.37, P < 0.01).

Fig 4
Multiple scatterplot between NK lymphocytes and DHT. C D 16 cell numbers were directly correlated with dihydrotestosterone (DHT) (Pearson's coefficient r = 0.86, P < 0.001) (• and continuous line).

A multivariate analysis of variance for evaluating alcohol and smoking effect on the correlations among these parameters was performed in 46 out of 62 subjects studied for whom information on drinking and smoking habits was available.

Cigarette smoking and alcohol consumption did not influence or modify any of the correlations examined so far.

1,25(OH2)D3 and i-PTH were correlated with CD16 number (Fig. 5a,b), with a correlation with vitamin D more evident for men (Pearson's coefficient r = 0.50, P < 0.014) and with i-PTH for women (Pearson's coefficient r = –0.44, P < 0.01) (not shown), while no individual correlation was found with immune parameters for GH and IGF-I.

Fig 5
Multiple scatterplot among NK lymphocytes, vitamin D and intact parathyroid hormone (i-PTH). (a) A direct correlation was found between CD16 cell numbers and vitamin D (Pearson's coefficient r = 0.40, P < 0.01), following a quadratic curve (R ...

The best fit of correlation between NK cell number and vitamin D was a quadratic curve (P < 0.01) that was represented by the following equation: %CD16 = (1.80 (vitamin D concentration) − 0.04(vitamin D concentration)2).

The increase in vitamin D amount paralleled the increase in CD16 lymphocytes up to 30%. Beyond this number, high concentrations of vitamin D were only apparently inhibitory, because the range amounts of the vitamin found in serum of these subjects were similar (10–35 pg/ml for 20–30% CD16 interval and 5–41 pg/ml for 30–40% CD16 interval).

In addition, vitamin D was also correlated with cytolytic activity for 100:1 effector:target cell ratio E:T 100 (Fig. 5c) following a logarithmic model represented by the equation: E/T100 = 16.3 ln (vitamin D concentration).

As determined by multivariate analysis of variance, the relation between vitamin D and number and functional activity of CD16 cells remained significant even after the addition of smoking and drinking to the model (P < 0.001). Only the habits of both smoking and drinking showed a small significant influence on this model (P = 0.048), but were less important than the influence exerted by vitamin D (P = 0.034), as determined by the sum of squares.

No sex influence was observed among correlations of vitamin D with cytolytic activity.

Nutritional status parameters of the studied subjects are listed in Table 2. Among these parameters, only AMA was directly correlated with NK cell number (Fig. 6a), while the indicators of fat reserves (AFA and TST) were linked to vitamin D amounts (Fig. 6b). A decrease of AMA was observed with increasing age both in men and women (Fig. 6a).

Fig 6
Multiple scatterplot among anthropometric parameters, NK lymphocytes, vitamin D and age. (a) A conserved muscular mass (AMA) was positively correlated with increasing CD16 cell numbers (Pearson's coefficient r = 0.35, P < 0.01) (• and ...
Table 2
Nutritional status in the study subjects

A multivariate analysis of variance, grouping the influence of anthropometric parameters and vitamin D on NK cell number, displayed a significant model (P < 0.01) in which each variable retained its influence (P < 0.03 at least) and the addition of smoking and/or drinking habits did not modify the significance of the model (P < 0.01).

The majority of the subjects of both sexes were not depressed (60% with GDS score < 11) or mildly depressed (27% with a GDS score between 11 and 20). GDS was inversely correlated with age (Spearman's coefficient r = −0.44, P < 0.03) only in males, but not with anthropometric indices or immune parameters.

Cognitive function (MMSE) was below normal range in almost all subjects (58 out of 62 studied: in general the lowest scores (< 11) were displayed by women (73%), the highest (scores 12–22) by men (44%) without correlating with immune parameters and anthropometric indices. Although MMSE is the most widely used cognitive screening test, its specificity decreases with age and it is strongly affected by educational level [41]. As clinical dementia was an exclusion criterion, generation background factors (poor formal education, reduced compliance with testing procedures) along with a high prevalence of sensory impairments may be respon-sible for the very poor MMSE performances of the subjects studied.

The ability to perform the basic ADL was retained in about 39% of the subjects studied (score < 2, at least one deficit), while 53% of the total population was dependent in many functions (scores 5–7) (χ2 not significant between women and men), but in general a high level of disability (ADL) was correlated with a low muscular mass (AMA) (Spearman's coefficient r = –0.33, P = 0.01) and a trend toward low vitamin D and a decrease in CD16 number even though these failed to reach significance.

Functional capacity decreased with the loss of cognitive function (MMSE) (Spearman's coefficient r = −0.40, P < 0.001) but not with symptoms of depression (Spearman's coefficient r =−0.30, P < 0.05); on the contrary, the most depressed subjects were those with preserved cognitive function (Spearman's coefficient r = 0.3, P < 0.05).

The principal component analysis was performed after checking the sample adequacy (Keiser Meyer Olkin test > 0.61) and five groups of consecutive factors were extracted with eigenvalues > 1 (explained variance 68.5% and varimax rotation) (Table 3).

Table 3
Principal component analysis

Vitamin D was extracted as the first component, together with calorie reserves (as TST and AFA) and also as fifth component together with NK cell immune function (CD16 and E/T100), that are negatively influenced by cigarette smoking.

The second principal component was sex, on which the different distribution of muscular mass (AMA) depends in males and females. The third principal component was represented by T3 and FT4 thyroid hormones, affecting the number of NK cells. Finally, the fourth component was alcohol consumption, which was joined with depression and functional capacity.


This study revealed that the group of oldest subjects with the highest number of NK cells and the best preserved cytolytic function also present a preserved metabolism of thyroid hormones and vitamin D and integrity of muscle mass.

In fact the NK cell number and/or cytolytic activity of healthy subjects > 90 years old was positively associated with serum level of vitamin D, while T3, FT4, i-PTH hormones and lean body mass were associated only with NK cell number.

Our previous studies disclosed twice as many NK cells from Senieur old people compared with young (about 30% versus 15%) [79]. In this study we have an apparently different distribution of NK cells, because the population we studied was characterized by ‘nearly’ Senieur parameters and by an extreme age interval (90–106 years) that probably influences a less homogeneous distribution of NK cell number.

The identification of this group of ‘naturally selected’ centenarians confirms the validity of the ‘Senieur protocol’ and the representativity of the population selected using ‘Senieur criteria’ for the studies of immune gerontology.

In addition, these data confirm our previous hypothesis that with advancing age the progressive increase in NK cell number compensates for a decreased number and function of T cells [7].

In agreement are the data obtained in mice, where the proportion of CD4 memory T cells was a strong predictor of lifespan [42], and in human longitudinal studies where a positive association was found between good T cell function in vitro, preserved CD4/CD8 T cell ratio and individual longevity. Further supporting evidence is the demonstration that CD4 lymphopenia in the oldest resulted in a two-fold increased mortality risk over the first 2 years following laboratory determination [43]. In the oldest the simplest innate immune functions such as NK natural immunity are probably more resistant and preserved for a long time, whereas the more complex T cell ones are modified or decreased, as suggested by Cossarizza [44].

Much data have accumulated on the existence of receptors for thyroid hormones on lymphocytes or the frequent immune alterations in physiological and pathological fluctuations in thyroid hormones [45]. TSH acts by restoring the reduced IL-2-induced NK activity present in lymphocytes from old subjects, low T3 serum levels have been associated with a reduced mitogen response and altered T cell subsets (frequently demonstrated in old subjects), while T4 reduced NK cell activity but not cell number [46].

Glucocorticoids are the most important inhibitors of immunological response [47] and cortisol is the most representative endogenous glucocorticoid in humans [24]. Cortisol effect is apparent at physiological concentrations of the hormone and regulates NK activity by repression of granzyme A (a component of NK lytic granules) synthesis. However, recent data suggest that the glucocorticoid inhibitory effect on immune response is reduced in the elderly and even more so in Alzheimer's disease [48], and that a peripheral glucocorticoid resistance develops with advancing age.

A poor vitamin D status is frequently encountered in elderly people [49]. The significant association of NK number and activity with vitamin D stores is of great concern, and is consistent with the observations in vitro that vitamin D deficiency in humans and animals is associated with reduced non-specific immune responses, with the in vivo evidence that supplementation of 1,25(OH2)D3 to elderly subjects significantly increases the circulating levels of interferon-alpha (IFN-α), one of the cytokines involved in modulating NK activity [50]. In addition, vitamin D enhances the differentiation and proliferation of cells that possess the corresponding receptor. These activities may be responsible for anti-neoplastic effects, since vitamin D, together with retinoids and IL-12, is a potent inhibitor of angiogenesis induced by tumour cells [51]. The anti-tumour effectiveness of IL-12 involves multiple other factors such as the activation and expansion of cellular immune circuits (activation of monocytes and macrophages as well stimulation of LAK activity against tumours) and the production of additional cytokines affecting chemotactic activity or nitric oxide involved in anti-tumour cellular cytotoxic mechanisms. Therefore, it is possible that the preserved amount of vitamin D and NK number protect these subjects from the development of tumours until extreme old age.

Furthermore, vitamin D binding to an intracellular binding protein (retinoic acid binding protein) belonging to the same superfamily as thyroid hormone and retinol nuclear receptors, suggests close interactions between the various hormonal systems [52].

The involvement of sex hormones in regulating the immune response is widely reported and our results confirm that androgens influence immune responses, as demonstrated by the correlation between DHT level and NK number. In contrast, the magnitude and significance of oestrogen action on the immune system seems less important, probably because in men the modification of these hormones occurs gradually over a longer period than in female gonads, where major modifications have been demonstrated but in less aged women.

Low levels of DHEAS have recently been associated with an increased cardiovascular risk and death from all causes in men as well as with high degrees of functional dependence in ADL [53], as also determined by our data.

Some studies [54, 55] have pointed out that body mass erosion is a fundamental part of normal ageing. Both protein and a variety of specific micronutrient deficits lead to or parallel a metabolic insufficiency that extends to lymphocytes and mononuclear cells impairing specific host defences.

In adults prognostic indices that include both immune and nutritional measures are reasonably sensitive and specific in predicting mortality and complications in hospitalized patients and in the apparently healthy free-living elderly. The close correlation between the degree of malnutrition and immunodeficiency in the elderly may increase the risk of infection, as demonstrated by the high number of non-responders (30–40%) among undernourished aged subjects who received influenza vaccination [56].

In conclusion, our results stress the paramount importance of nutritional evaluation in the clinical assessment of elderly people and suggest that avoiding alcohol intake and not smoking tend to be associated with a preserved NK lytic activity even in very advanced age.

We can conclude that becoming centenarians is a multifactorial process, where not only the immune system but also numerous other physiological systems decline, resulting in the loss or decrease of adaptation capacity. In fact, metabolic decompensation that would be easily tolerated in a young subject can lead to problems for older people, although long-lived individuals are likely to maintain their residual homeostatic reserve capacity at its best. A better understanding of the causes of immunosenescence may offer the possibility of therapeutic intervention and may result in a significant reduction in the cost of medical care in old age.


This work was partially supported by grants from M.U.R.S.T. (60% fund), from Ricerca Corrente I.O.R. and was performed under the aegis of the European Union Concerted Action on the Molecular Biology of Immunosenescence EUCAMBIS (contract BWHI-CT94-1209). The authors thank Anne Collins for revising the English manuscript, Patrizia Rappini and Graziella Salmi for editorial assistance.


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